Substituted dipyrido[1,2-a:1′,2′-d]pyrazines for treating viral infections

ABSTRACT

Compounds for use in the treatment of human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following Formula (I): 
                         
including stereoisomers and pharmaceutically acceptable salts thereof, wherein L, R 1 , R 5 , W, X, Y 1 , Y 2 , and Z are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

This Application is a Continuation of application Ser. No. 15/257,528filed on Sep. 6, 2016. Application Ser. No. 15/257,528 is a Division ofapplication Ser. No. 14/329,697 filed on Jul. 11, 2014. Application Ser.No. 14/329,697 claims the benefit of U.S. Provisional Application61/845,807 filed on Jul. 12, 2013. The entire contents of theseapplications are incorporated herein by reference in their entirety.

BACKGROUND Field

Compounds, compositions, and methods for the treatment of humanimmunodeficiency virus (HIV) infection are disclosed. In particular,novel polycyclic carbamoylpyridone compounds and methods for theirpreparation and use as therapeutic or prophylactic agents are disclosed.

Description of the Related Art

Human immunodeficiency virus infection and related diseases are a majorpublic health problem worldwide. Human immunodeficiency virus type 1(HIV-1) encodes three enzymes which are required for viral replication:reverse transcriptase, protease, and integrase. Although drugs targetingreverse transcriptase and protease are in wide use and have showneffectiveness, particularly when employed in combination, toxicity anddevelopment of resistant strains have limited their usefulness (Palella,et al. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001)410:995-1001).

A goal of antiretroviral therapy is to achieve viral suppression in theHIV infected patient. Current treatment guidelines published by theUnited States Department of Health and Human Services provide thatachievement of viral suppression requires the use of combinationtherapies, i.e., several drugs from at least two or more drug classes.(Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the use of antiretroviral agents in HIV-1-infected adultsand adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Sectionaccessed Mar. 14, 2013.) In addition, decisions regarding the treatmentof HIV infected patients are complicated when the patient requirestreatment for other medical conditions (Id. at E-12). Because thestandard of care requires the use of multiple different drugs tosuppress HIV, as well as to treat other conditions the patient may beexperiencing, the potential for drug interaction is a criterion forselection of a drug regimen. As such, there is a need for antiretroviraltherapies having a decreased potential for drug interactions.

Accordingly, there is a need for new agents that inhibit the replicationof HIV and that minimize the potential for drug-drug interactions whenco-administered with other drugs.

BRIEF SUMMARY

The present invention is directed to novel polycyclic carbamoylpyridonecompounds, having antiviral activity, including stereoisomers andpharmaceutically acceptable salts thereof, and the use of such compoundsin the treatment of HIV infections. The compounds of the invention maybe used to inhibit the activity of HIV integrase and may be used toreduce HIV replication.

In one embodiment of the present invention, compounds having thefollowing Formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof,

-   -   wherein:

Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;

R¹ is phenyl substituted with one to three halogens;

X is —CHR²—;

W is a bond or —CHR³—;

Z is a bond or —CHR⁴—;

R², R³, and R⁴ are each, independently, hydrogen or C₁₋₃alkyl;

R⁵ is hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;

L is —C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂— or —C(R^(a))₂C(R^(a))₂C(R^(a))₂—;and

each R^(a) is, independently, hydrogen, halo, hydroxyl or C₁₋₄alkyl.

In another embodiment of the present invention, compounds having thefollowing Formula (I-A) are provided:

or a stereoisomer or pharmaceutically acceptable salt thereof,wherein:

Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl,or Y¹ and Y², together with the carbon atom to which they are attached,form a carbocyclic ring having from 3 to 6 ring atoms or a heterocyclicring having from 3 to 6 ring atoms, wherein the carbocyclic orheterocyclic ring is optionally substituted with one or more R^(a);

R¹ is optionally substituted aryl or optionally substituted heteroaryl;

X is —O— or —NR²— or —CHR²—;

W is a bond, —O— or —NR³— or —CHR³—;

Z is a bond or —CHR⁴—;

R², R³ and R⁴ are each, independently, hydrogen or C₁₋₃alkyl;

L

is —C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂C(R^(a))₂C(R^(a))₂—, —C(R^(a))₂OC(R^(a))₂—,—C(R^(a))₂NR^(a)C(R^(a))₂—, —C(R^(a))₂SC(R^(a))₂—,—C(R^(a))₂S(O)C(R^(a))₂—, —C(R^(a))₂SO₂C(R^(a))₂—,—C(R^(a))₂OC(R^(a))₂C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂OC(R^(a))₂—,—C(R^(a))₂NR^(a)C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂NR^(a)C(R^(a))₂—, —C(R^(a))₂SC(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂SC(R^(a))₂—, —C(R^(a))₂S(O)C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂S(O)C(R^(a))₂—, —C(R^(a))₂SO₂C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂SO₂C(R^(a))₂—, —C(R^(a))₂SO₂NR^(a)C(R^(a))₂— or—C(R^(a))₂NR^(a)SO₂C(R^(a))₂—; and

each R^(a) is, independently, hydrogen, halo, hydroxyl or C₁₋₄alkyl, orwherein two R^(a) groups, together with the carbon atom to which theyare attached, form C═O.

In a further embodiment, compounds are provided having the followingFormula (I-B):

or a stereoisomer or pharmaceutically acceptable salt thereof,

-   -   wherein:

Y¹ and Y² are each, independently, hydrogen, C₁₋₃ alkyl orC₁₋₃haloalkyl;

R¹ is phenyl substituted with one to three halogens;

X is —CHR²—;

W is a bond or —CHR³—;

Z is a bond or —CHR⁴—;

R², R³, and R⁴ are each, independently, hydrogen or C₁₋₃alkyl;

L is —C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂— or —C(R^(a))₂C(R^(a))₂C(R^(a))₂—;and

each R^(a) is, independently, hydrogen, halo, hydroxyl or C₁₋₄alkyl.

In another embodiment, compounds are provided having the followingFormula (II):

In a further embodiment, compounds are provided having the followingFormula (II-A):

In another embodiment, compounds are provided having the followingFormula (III):

In a further embodiment, compounds are provided having the followingFormula (III-A):

In another embodiment, compounds are provided having the followingFormula (IV):

In a further embodiment, compounds are provided having the followingFormula (IV-A):

In another embodiment, L is —C(R^(a))₂—. In a further embodiment, L is—C(R^(a))₂C(R^(a))₂—. In still a further embodiment, L is—C(R^(a))₂C(R^(a))₂C(R^(a))₂—. In still a further embodiment, each IV ishydrogen.

In another embodiment, R¹ is substituted with one halogen. In a furtherembodiment, R¹ is 4-fluorophenyl or 2-fluorophenyl.

In another embodiment, R¹ is substituted with two halogens. In a furtherembodiment, R¹ is 2,4-difluorophenyl, 2,3-difluorophenyl,2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl,2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In still a furtherembodiment, R¹ is 2,4-difluorophenyl.

In another embodiment, R¹ is substituted with three halogens. In afurther embodiment, R¹ is 2,4,6-trifluorophenyl or2,3,4-trifluorophenyl. In still a further embodiment, R¹ is2,4,6-trifluorophenyl.

In yet another embodiment compounds are provided having the followingstructures:

In another embodiment, a pharmaceutical composition is providedcomprising a compound having Formula (I), (I-A), (I-B), (II), (II-A),(III), (III-A), (IV), (IV-A), or a stereoisomer or pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,diluent or excipient.

The invention also provides the use of a pharmaceutical composition asdescribed hereinabove for the treatment of an HIV infection in a humanbeing having or at risk of having the infection.

In another embodiment, a method of using a compound having Formula (I),(I-A), (I-B), (II), (II-A), (III), (III-A), (IV), (IV-A), or astereoisomer or pharmaceutically acceptable salt thereof, in therapy isprovided. In particular, a method of treating the proliferation of theHIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptomsin a mammal (e.g. a human) is provided, comprising administering to themammal a compound having Formula (I), (I-A), (I-B), (II), (II-A), (III),(III-A), (IV), (IV-A) or a stereoisomer or pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, diluent orexcipient.

In another embodiment, use of a compound of Formula (I), (I-A), (I-B),(II), (II-A), (III), (III-A), (IV), or (IV-A), as described herein, or apharmaceutically acceptable salt thereof, for the treatment of an HIVinfection in a human being having or at risk of having the infection isdisclosed.

In another embodiment, the use of a compound of Formula (I), (I-A),(I-B), (II), (II-A), (III), (III-A), (IV), or (IV-A), as describedherein, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of an HIV infection in ahuman being having or at risk of having the infection is disclosed.

In another embodiment, an article of manufacture comprising acomposition effective to treat an HIV infection; and packaging materialcomprising a label which indicates that the composition can be used totreat infection by HIV is disclosed. Exemplary compositions comprise acompound of Formula (I), (I-A), (I-B), (II), (II-A), (III), (III-A),(IV), or (IV-A), according to this invention or a pharmaceuticallyacceptable salt thereof.

In still another embodiment, a method of inhibiting the replication ofHIV is disclosed. The method comprises exposing the virus to aneffective amount of the compound of Formula (I), (I-A), (I-B), (II),(II-A), (III), (III-A), (IV), or (IV-A) or a salt thereof, underconditions where replication of HIV is inhibited.

In another embodiment, the use of a compound of Formula (I), (I-A),(I-B), (II), (II-A), (III), (III-A), (IV), (IV-A), or a pharmaceuticallyacceptable salt thereof to inhibit the activity of the HIV integraseenzyme is disclosed.

In another embodiment, the use of a compound of Formula (I), (I-A),(I-B), (II), (II-A), (III), (III-A), (IV), (IV-A), or a salt thereof, toinhibit the replication of HIV is disclosed.

Other embodiments, objects, features and advantages will be set forth inthe detailed description of the embodiments that follows, and in partwill be apparent from the description, or may be learned by practice, ofthe claimed invention. These objects and advantages will be realized andattained by the processes and compositions particularly pointed out inthe written description and claims hereof. The foregoing Summary hasbeen made with the understanding that it is to be considered as a briefand general synopsis of some of the embodiments disclosed herein, isprovided solely for the benefit and convenience of the reader, and isnot intended to limit in any manner the scope, or range of equivalents,to which the appended claims are lawfully entitled.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details. The description belowof several embodiments is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience only and are not to be construedto limit the claims in any way. Embodiments illustrated under anyheading may be combined with embodiments illustrated under any otherheading.

Definitions

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to”.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁-C₁₂ alkyl), preferably one toeight carbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆alkyl), and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. In certain embodiments, “Alkyl” refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, which is saturated, having from one to twelve carbon atoms(C₁-C₁₂ alkyl), or from one to eight carbon atoms (C₁-C₈ alkyl), or fromone to six carbon atoms (C₁-C₆ alkyl), or from one to four carbon atoms(C₁-C₄ alkyl), and which is attached to the rest of the molecule by asingle bond. Unless stated otherwise specifically in the specification,an alkyl group may be optionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds), andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, ethenylene, propenylene, n-butenylene,propynylene, n-butynylene, and the like. The alkylene chain is attachedto the rest of the molecule through a single or double bond and to theradical group through a single or double bond. The points of attachmentof the alkylene chain to the rest of the molecule and to the radicalgroup can be through one carbon or any two carbons within the chain.Unless stated otherwise specifically in the specification, an alkylenechain may be optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(A) where R_(A) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, an alkoxygroup may be optionally substituted.

“Alkylamino” refers to a radical of the formula —NHR_(A) or —NR_(A)R_(A)where each R_(A) is, independently, an alkyl radical as defined abovecontaining one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkylamino group may be optionallysubstituted.

“Thioalkyl” refers to a radical of the formula —SR_(A) where R_(A) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, a thioalkylgroup may be optionally substituted.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems. In a preferred embodiment, the aryl radical is amonocyclic ring system. Aryl radicals include, but are not limited to,aryl radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene,fluorene, as-indacene, s-indacene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unlessstated otherwise specifically in the specification, the term “aryl” orthe prefix “ar-” (such as in “aralkyl”) is meant to include arylradicals that are optionally substituted.

“Aralkyl” refers to a radical of the formula —R_(B)—R_(C) where R_(B) isan alkylene chain as defined above and R_(C) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. Unless stated otherwise specifically in the specification, anaralkyl group may be optionally substituted.

“Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromaticmonocyclic or polycyclic hydrocarbon radical consisting solely of carbonand hydrogen atoms, which may include fused or bridged ring systems,having from three to fifteen carbon atoms, preferably having from threeto ten carbon atoms, and which is saturated or unsaturated and attachedto the rest of the molecule by a single bond. In certain preferredembodiments, “Cycloalkyl” or “carbocyclic ring” refers to a stablenon-aromatic monocyclic hydrocarbon radical consisting solely of carbonand hydrogen atoms, having from three to fifteen carbon atoms, or havingfrom three to ten carbon atoms, or having from three to eight carbonatoms and which is saturated or unsaturated and attached to the rest ofthe molecule by a single bond Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.Unless otherwise stated specifically in the specification, a cycloalkylgroup may be optionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(B)R_(D) whereR_(B) is an alkylene chain as defined above and R_(D) is a cycloalkylradical as defined above. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group may be optionally substituted.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group may be optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to18-membered non-aromatic ring radical which consists of two to twelvecarbon atoms and from one to six heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur. Unless stated otherwisespecifically in the specification, the heterocyclyl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heterocyclyl radical may be optionally oxidized; thenitrogen atom may be optionally quatemized; and the heterocyclyl radicalmay be partially or fully saturated. In certain preferred embodiments,the heterocyclyl radical is a monocyclic ring system; and/or thenitrogen, carbon or sulfur atoms in the heterocyclyl radical isoptionally oxidized; and/or the nitrogen atom is optionally quaternized.Examples of such heterocyclyl radicals include, but are not limited to,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group may be optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, an N-heterocyclyl group may beoptionally substituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(B)R_(E) whereR_(B) is an alkylene chain as defined above and R_(E) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. Unless stated otherwisespecifically in the specification, a heterocyclylalkyl group may beoptionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; the nitrogen, carbon or sulfur atoms in the heteroaryl radicalmay be optionally oxidized; and the nitrogen atom may be optionallyquaternized. In certain preferred embodiments, the heteroaryl radical isa monocyclic ring system; and/or the nitrogen, carbon or sulfur atoms inthe heteroaryl radical is optionally oxidized; and/or the nitrogen atomis optionally quaternized. Examples include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl,benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group may be optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(B)R_(F) whereR_(B) is an alkylene chain as defined above and R_(F) is a heteroarylradical as defined above. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group may be optionally substituted.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl)wherein at least one hydrogen atom is replaced by a bond to anon-hydrogen atoms such as, but not limited to: a halogen atom such asF, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups,alkoxy groups, and ester groups; a sulfur atom in groups such as thiolgroups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxidegroups; a nitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl,and ester groups; and nitrogen in groups such as imines, oximes,hydrazones, and nitriles. For example, “substituted” includes any of theabove groups in which one or more hydrogen atoms are replaced with—NR_(G)R_(H), —NR_(G)C(═O)R_(H), —NR_(G)C(═O)NR_(G)R_(H),—NR_(G)C(═O)OR_(H), —NR_(G)C(═NR_(g))NR_(G)R_(H), —NR_(G) SO₂R_(H),—OC(═O)NR_(G)R_(H), —OR_(G), —SR_(G), —SOR_(G), —SO₂R_(G), —OSO₂R_(G),—SO₂OR_(G), NSO₂R_(G), and —SO₂NR_(G)R_(H). “Substituted” also means anyof the above groups in which one or more hydrogen atoms are replacedwith —C(═O)R_(G), —C(═O)OR_(G), —C(═O)NR_(G)R_(H), —CH₂SO₂R_(G),—CH₂SO₂NR_(G)R_(H). In the foregoing, R_(G) and R_(H) are the same ordifferent and independently hydrogen, alkyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any ofthe above groups in which one or more hydrogen atoms are replaced by abond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo,alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkylgroup. In addition, each of the foregoing substituents may also beoptionally substituted with one or more of the above substituents.

The term “protecting group,” as used herein, refers to a labile chemicalmoiety which is known in the art to protect reactive groups includingwithout limitation, hydroxyl and amino groups, against undesiredreactions during synthetic procedures. Hydroxyl and amino groupsprotected with a protecting group are referred to herein as “protectedhydroxyl groups” and “protected amino groups”, respectively. Protectinggroups are typically used selectively and/or orthogonally to protectsites during reactions at other reactive sites and can then be removedto leave the unprotected group as is or available for further reactions.Protecting groups as known in the art are described generally in Greeneand Wuts, Protective Groups in Organic Synthesis, 3rd edition, JohnWiley & Sons, New York (1999). Generally, groups are protected orpresent as a precursor that will be inert to reactions that modify otherareas of the parent molecule for conversion into their final groups atan appropriate time. Further representative protecting or precursorgroups are discussed in Agrawal, et al., Protocols for OligonucleotideConjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp. 1-72.Examples of “hydroxyl protecting groups” include, but are not limitedto, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl,p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl,diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl (TBDPS),triphenylsilyl, benzoylformate, acetate, chloroacetate,trichloroacetate, trifluoroacetate, pivaloate, benzoate,p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and tosylate.Examples of “amino protecting groups” include, but are not limited to,carbamate-protecting groups, such as 2-trimethylsilylethoxycarbonyl(Teoc), 1-methyl-1-(4-biphenylyl)ethoxy carb onyl (Bpoc), t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl(Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups, such asformyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl;sulfonamide-protecting groups, such as 2-nitrobenzenesulfonyl; and imineand cyclic imide protecting groups, such as phthalimido anddithiasuccinoyl.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of Formula (I), (I-A), (I-B),(II), (II-A), (III), (III-A), (IV), (IV-A), and stereoisomers orpharmaceutically acceptable salts thereof, being isotopically-labeled byhaving one or more atoms replaced by an atom having a different atomicmass or mass number. Examples of isotopes that can be incorporated intothe disclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I,and ¹²⁵I, respectively. These radiolabeled compounds could be useful tohelp determine or measure the effectiveness of the compounds, bycharacterizing, for example, the site or mode of action, or bindingaffinity to pharmacologically important site of action. Certainisotopically-labeled compounds of Formula (I), (I-A), (I-B), (II),(II-A), (III), (III-A), (IV), (IV-A), and stereoisomers orpharmaceutically acceptable salts thereof for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability. For example, in vivo half-life may increase or dosagerequirements may be reduced. Thus, heavier isotopes may be preferred insome circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof Formula (I), (I-A), (I-B), (II), (II-A), (III), (III-A), (IV),(IV-A), and stereoisomers or pharmaceutically acceptable salts thereof,can generally be prepared by conventional techniques known to thoseskilled in the art or by processes analogous to those described in theExamples as set out below using an appropriate isotopically-labeledreagent in place of the non-labeled reagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabeled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

Examples of “pharmaceutically acceptable salts” of the compoundsdisclosed herein include salts derived from an appropriate base, such asan alkali metal (for example, sodium), an alkaline earth metal (forexample, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl).Pharmaceutically acceptable salts of a nitrogen atom or an amino groupinclude for example salts of organic carboxylic acids such as acetic,benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric,phosphoric and sulfamic acids. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein X isindependently selected from H or a C₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of Formula (I), (I-A), (I-B), (II), (II-A),(III), (III-A), (IV), (IV-A), a stereoisomer or pharmaceuticallyacceptable salt thereof, or another compound of the invention. Allsalts, whether or not derived from a physiologically acceptable acid orbase, are within the scope of the present invention.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines. Finally, it is to beunderstood that the compositions herein comprise compounds disclosedherein in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Effective amount” or “therapeutically effective amount” refers to anamount of a compound according to the invention, which when administeredto a patient in need thereof, is sufficient to effect treatment fordisease-states, conditions, or disorders for which the compounds haveutility. Such an amount would be sufficient to elicit the biological ormedical response of a tissue system, or patient that is sought by aresearcher or clinician. The amount of a compound according to theinvention which constitutes a therapeutically effective amount will varydepending on such factors as the compound and its biological activity,the composition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of the treatment, the type of disease-state or disorder beingtreated and its severity, drugs used in combination with orcoincidentally with the compounds of the invention, and the age, bodyweight, general health, sex and diet of the patient. Such atherapeutically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, thestate of the art, and this disclosure.

The term “treatment” as used herein is intended to mean theadministration of a compound or composition according to the presentinvention to alleviate or eliminate symptoms of HIV infection and/or toreduce viral load in a patient. The term “treatment” also encompassesthe administration of a compound or composition according to the presentinvention post-exposure of the individual to the virus but before theappearance of symptoms of the disease, and/or prior to the detection ofthe virus in the blood, to prevent the appearance of symptoms of thedisease and/or to prevent the virus from reaching detectible levels inthe blood, and the administration of a compound or composition accordingto the present invention to prevent perinatal transmission of HIV frommother to baby, by administration to the mother before giving birth andto the child within the first days of life.

The term “antiviral agent” as used herein is intended to mean an agent(compound or biological) that is effective to inhibit the formationand/or replication of a virus in a human being, including but notlimited to agents that interfere with either host or viral mechanismsnecessary for the formation and/or replication of a virus in a humanbeing.

The term “inhibitor of HIV replication” as used herein is intended tomean an agent capable of reducing or eliminating the ability of HIV toreplicate in a host cell, whether in vitro, ex vivo or in vivo.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

Compounds

As noted above, in one embodiment of the present invention, compoundsare provided having the following Formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof,

-   -   wherein:

Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;

R¹ is phenyl substituted with one to three halogens;

X is —CHR²—;

W is a bond or —CHR³—;

Z is a bond or —CHR⁴—;

R², R³, and R⁴ are each, independently, hydrogen or C₁₋₃alkyl;

R⁵ is hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;

L is —C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂— or —C(R^(a))₂C(R^(a))₂C(R^(a))₂—;and

each R^(a) is, independently, hydrogen, halo, hydroxyl or C₁₋₄alkyl.

In another embodiment of the present invention, compounds having thefollowing Formula (I-A) are provided:

or a stereoisomer or pharmaceutically acceptable salt thereof,wherein:

Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl,or Y¹ and Y², together with the carbon atom to which they are attached,form a carbocyclic ring having from 3 to 6 ring atoms or a heterocyclicring having from 3 to 6 ring atoms, wherein the carbocyclic orheterocyclic ring is optionally substituted with one or more R^(a);

R¹ is optionally substituted aryl or optionally substituted heteroaryl;

X is —O— or —NR²— or —CHR²—;

W is a bond, —O— or —NR³— or —CHR³—;

Z is a bond or —CHR⁴—;

R², R³ and R⁴ are each, independently, hydrogen or C₁₋₃alkyl;

L

is —C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂C(R^(a))₂C(R^(a))₂—, —C(R^(a))₂OC(R^(a))₂—,—C(R^(a))₂NR^(a)C(R^(a))₂—, —C(R^(a))₂SC(R^(a))₂—,—C(R^(a))₂S(O)C(R^(a))₂—, —C(R^(a))₂SO₂C(R^(a))₂—,—C(R^(a))₂OC(R^(a))₂C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂OC(R^(a))₂—,—C(R^(a))₂NR^(a)C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂NR^(a)C(R^(a))₂—, —C(R^(a))₂SC(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂SC(R^(a))₂—, —C(R^(a))₂S(O)C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂S(O)C(R^(a))₂—, —C(R^(a))₂SO₂C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂SO₂C(R^(a))₂—, —C(R^(a))₂SO₂NR^(a)C(R^(a))₂— or—C(R^(a))₂NR^(a)SO₂C(R^(a))₂—; and

each R^(a) is, independently, hydrogen, halo, hydroxyl or C₁₋₄alkyl, orwherein two R^(a) groups, together with the carbon atom to which theyare attached, form C═O.

In a further embodiment, compounds are provided having the followingFormula (I-B):

or a stereoisomer or pharmaceutically acceptable salt thereof,

-   -   wherein:

Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;

R¹ is phenyl substituted with one to three halogens;

X is —CHR²—;

W is a bond or —CHR³—;

Z is a bond or —CHR⁴—;

R², R³, and R⁴ are each, independently, hydrogen or C₁₋₃alkyl;

L is —C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂— or —C(R^(a))₂C(R^(a))₂C(R^(a))₂—;and

each R^(a) is, independently, hydrogen, halo, hydroxyl or C₁₋₄alkyl.

In another embodiment, compounds are provided having the followingFormula (II):

In a further embodiment, compounds are provided having the followingFormula (II-A):

In another embodiment, compounds are provided having the followingFormula (III):

In a further embodiment, compounds are provided having the followingFormula (III-A):

In another embodiment, compounds are provided having the followingFormula (IV):

In a further embodiment, compounds are provided having the followingFormula (IV-A):

In another embodiment, L is —C(R^(a))₂—. In a further embodiment, L is—C(R^(a))₂C(R^(a))₂—. In still a further embodiment, L is—C(R^(a))₂C(R^(a))₂C(R^(a))₂—.

In a certain embodiment, each R^(a) is, independently, hydrogen, halo,hydroxyl or methyl. In a certain embodiment, each R^(a) is,independently, hydrogen or methyl. In still a further embodiment, eachR^(a) is hydrogen.

In another embodiment, R¹ is substituted with one halogen. In a furtherembodiment, R¹ is 4-fluorophenyl or 2-fluorophenyl.

In another embodiment, R¹ is substituted with two halogens. In a furtherembodiment, R¹ is 2,4-difluorophenyl, 2,3-difluorophenyl,2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl,2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In still a furtherembodiment, R¹ is 2,4-difluorophenyl.

In another embodiment, R¹ is substituted with three halogens. In afurther embodiment, R¹ is 2,4,6-trifluorophenyl or2,3,4-trifluorophenyl. In still a further embodiment, R¹ is2,4,6-trifluorophenyl.

In a certain embodiment, Y¹ and Y² are each, independently, hydrogen,methyl, CF₂ or CF₃. In a certain embodiment, Y¹ and Y² are each,independently, hydrogen or methyl.

In a certain embodiment, X is —CHR²—; W is —CHR³—; and Z is —CHR⁴—. In acertain embodiment, X is —CHR²—; W is a bond; and Z is —CHR⁴—. In acertain embodiment, X is —CHR²—; W is —CHR³—; and Z is a bond.

In a certain embodiment, R², R³, and R⁴ are each, independently,hydrogen or methyl. In a certain embodiment, R², R³, and R⁴ are eachhydrogen.

In yet another embodiment of the present invention, compounds of any oneof Formulas (I), (I-A), (I-B), (II), (II-A), (III), (III-A), (IV), or(IV-A), or a stereoisomer or pharmaceutically acceptable salt thereof,having antiviral activity are provided.

In one embodiment, a pharmaceutical composition is provided comprising acompound of any one of Formulas (I), (I-A), (I-B), (II), (II-A), (III),(III-A), (IV), or (IV-A), or a stereoisomer or pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,diluent or excipient.

Another embodiment is provided comprising a method of treating orpreventing an HIV infection in a human having or at risk of having theinfection by administering to the human a therapeutically effectiveamount of a compound of any one of Formulas (I), (I-A), (I-B), (II),(II-A), (III), (III-A), (IV), or (IV-A), or a pharmaceutical compositionthereof.

In another embodiment, the use of a compound of any one of Formulas (I),(I-A), (I-B), (II), (II-A), (III), (III-A), (IV), or (IV-A), or apharmaceutical composition thereof, for the treatment or prevention ofan HIV infection in a human having or at risk of having the infection isprovided.

In another embodiment, the use in medical therapy of a compound of anyone of the Formulas (I), (I-A), (I-B), (II), (II-A), (III), (III-A),(IV), or (IV-A), or a pharmaceutical composition thereof, is provided.

In another embodiment, the use of a compound of any one of the Formulas(I), (I-A), (I-B), (II), (II-A), (III), (III-A), (IV), or (IV-A), or apharmaceutical composition thereof, for use in the prophylactic ortherapeutic treatment of an HIV infection is provided.

As further noted above, in another embodiment of the present invention,compounds having antiviral activity are provided, the compounds havingthe following Formula (I-A):

or a stereoisomer or pharmaceutically acceptable salt thereof,

-   -   wherein:

Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl,or Y¹ and Y², together with the carbon atom to which they are attached,form a carbocyclic ring having from 3 to 6 ring atoms or a heterocyclicring having from 3 to 6 ring atoms, wherein the carbocyclic orheterocyclic ring is optionally substituted with one or more R^(a);

R¹ is optionally substituted aryl or optionally substituted heteroaryl;

X is —O— or —NR²— or —CHR²—;

W is a bond, —O— or —NR³— or —CHR³—;

Z is a bond or —CHR⁴—;

R², R³ and R⁴ are each, independently, hydrogen or C₁₋₃alkyl;

L

is —C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂C(R^(a))₂—,—C(R^(a))C(R^(a))₂C(R^(a))₂C(R^(a))₂—, —C(R^(a))₂OC(R^(a))₂—,—C(R^(a))₂NR^(a)C(R^(a))₂—, —C(R^(a))₂SC(R^(a))₂—,—C(R^(a))₂S(O)C(R^(a))₂—, —C(R^(a))SO₂C(R^(a))₂—,—C(R^(a))₂OC(R^(a))₂C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂OC(R^(a))₂—,—C(R^(a))₂NR^(a)C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂NR^(a)C(R^(a))₂—, —C(R^(a))₂SC(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂SC(R^(a))₂—, —C(R^(a))₂S(O)C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂S(O)C(R^(a))₂—, —C(R^(a))₂SO₂C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂SO₂C(R^(a))₂—, —C(R^(a))₂SO₂NR^(a)C(R^(a))₂— or—C(R^(a))₂NR^(a)SO₂C(R^(a))₂—; and

each R^(a) is, independently, hydrogen, halo, hydroxyl or C₁₋₄alkyl, orwherein two R^(a) groups, together with the carbon atom to which theyare attached, form C═O.

In another embodiment, compounds are provided having one of thefollowing Formulas (II), (III), or (IV):

In another embodiment, compounds are provided having the followingFormula (IIA):

In another embodiment, compounds are provided having one of thefollowing Formulas (II-B), (II-C), (II-D) or (II-E):

In another embodiment, compounds are provided having one of thefollowing Formulas (II-F), (II-G), (II-H), or (II-I):

In another embodiment, compounds are provided having the followingFormula (III-A):

In another embodiment, compounds are provided having one of thefollowing Formulas (III-B), (III-C), (III-D) or (III-E):

In another embodiment, compounds are provided having one of thefollowing Formulas (III-F), (III-G), (III-H), or (III-I):

In another embodiment, compounds are provided having the followingFormula (IV-A):

In another embodiment, compounds are provided having one of thefollowing Formulas (IV-B), (IV-C), (IV-D) or (IV-E):

In another embodiment, compounds are provided having one of thefollowing Formulas (IV-F), (IV-G), (IV-H), or (IV-I):

In another embodiment, L is —C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂C(R^(a))₂—, or—C(R^(a))₂C(R^(a))₂C(R^(a))₂C(R^(a))₂—. In a further embodiment, L is—C(R^(a))₂—. In still a further embodiment, L is —C(R^(a))₂C(R^(a))₂—.In still a further embodiment, L is —C(R^(a))₂C(R^(a))₂C(R^(a))₂—. Instill a further embodiment, each R^(a) is hydrogen.

In another embodiment, L is —C(R^(a))₂OC(R^(a))₂—,—C(R^(a))₂NR^(a)C(R^(a))₂—, —C(R^(a))₂SC(R^(a))₂—,—C(R^(a))₂S(O)C(R^(a))₂—, or —C(R^(a))₂SO₂C(R^(a))₂—. In a furtherembodiment, each R^(a) is hydrogen.

In another embodiment, X is —O—. In another embodiment, X is —NH—. Inanother embodiment, X is —CH₂—.

In another embodiment, R¹ is phenyl. In another embodiment, R¹ ispyridinyl.

In another embodiment, R¹ is substituted with at least one halogen.

In another embodiment, R¹ is substituted with one halogen. In a furtherembodiment, R¹ is 4-fluorophenyl or 2-fluorophenyl.

In another embodiment, R¹ is substituted with two halogens. In a furtherembodiment, R¹ is 2,4-difluorophenyl, 2,3-difluorophenyl,2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl,2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In still a furtherembodiment, R¹ is 2,4-difluorophenyl.

In another embodiment, R¹ is substituted with three halogens. In afurther embodiment, R¹ is 2,4,6-trifluorophenyl or2,3,4-trifluorophenyl. In still a further embodiment, R¹ is2,4,6-trifluorophenyl.

In another embodiment, R¹ is 3-trifluoromethyl-4-fluorophenyl or2-cyclopropoxy-4-fluorophenyl.

In one embodiment, a pharmaceutical composition is provided comprising acompound of any one of Formulas (I), (I-A), (I-B), (II), (II-A), (II-B),(II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (III), (III-A),(III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I),(IV), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H),and (IV-I), or a stereoisomer or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, diluent orexcipient.

Another embodiment is provided comprising a method of treating orpreventing an HIV infection in a human having or at risk of having theinfection by administering to the human a therapeutically effectiveamount of a compound of any one of Formulas (I), (I-A), (I-B), (II),(II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I),(III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G),(III-H), (III-I), (IV), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F),(IV-G), (IV-H), and (IV-I), or a pharmaceutical composition thereof.

In another embodiment, the use of a compound of any one of Formulas (I),(I-A), (I-B), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F),(II-G), (II-H), (II-I), (III), (III-A), (III-B), (III-C), (III-D),(III-E), (III-F), (III-G), (III-H), (III-I), (IV), (IV-A), (IV-B),(IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and (IV-I), or apharmaceutical composition thereof for use in medical therapy. In aparticular embodiment, the medical therapy is prevention or treatment ofHIV infection in a patient. In a particular embodiment, the medicaltherapy is treatment of HIV infection in a patient.

In another embodiment, the use of a compound of any one of Formulas (I),(I-A), (I-B), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F),(II-G), (II-H), (II-I), (III), (III-A), (III-B), (III-C), (III-D),(III-E), (III-F), (III-G), (III-H), (III-I), (IV), (IV-A), (IV-B),(IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and (IV-I), or apharmaceutical composition thereof for the treatment or prevention of anHIV infection in a human having or at risk of having the infection.

In another embodiment the substituent groups of Formulas (I), (I-A),(I-B), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G),(II-H), (II-I), (III), (III-A), (III-B), (III-C), (III-D), (III-E),(III-F), (III-G), (III-H), (III-I), (IV), (IV-A), (IV-B), (IV-C),(IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and (IV-I), as set forth above,maybe defined as follows:

Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl,or Y¹ and Y², together with the carbon atom to which they are attached,form a carbocyclic ring having from 3 to 6 ring atoms or a heterocyclicring having from 3 to 6 ring atoms, wherein the carbocyclic orheterocyclic ring is optionally substituted with one or more R^(a);

R¹ is optionally substituted aryl or optionally substituted heteroaryl;

X is —O— or —NR²— or —CHR²—;

W is a bond, —O— or —NR³— or —CHR³—;

Z is a bond or —CHR⁴—;

R², R³ and R⁴ are each, independently, hydrogen or C₁₋₃alkyl;

L

is —C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂C(R^(a))₂C(R^(a))₂—, —C(R^(a))₂OC(R^(a))₂—,—C(R^(a))₂NR^(a)C(R^(a))₂—, —C(R^(a))₂SC(R^(a))₂—,—C(R^(a))₂S(O)C(R^(a))₂—, —C(R^(a))₂SO₂C(R^(a))₂—,—C(R^(a))₂OC(R^(a))₂C(R^(a))₂—, —C(R^(a))₂C(R^(a))₂OC(R^(a))₂—,—C(R^(a))₂NR^(a)(C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))NR^(a)(C(R^(a))₂—, —C(R^(a))₂SC(R^(a))₂C(R^(a))₂—,—C(R^(a))C(R^(a))₂SC(R^(a))₂—, —C(R^(a))₂S(O)C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂S(O)C(R^(a))₂—, —C(R^(a))₂SO₂C(R^(a))₂C(R^(a))₂—,—C(R^(a))₂C(R^(a))₂SO₂C(R^(a))₂—, —C(R^(a))₂SO₂NR^(a)C(R^(a))₂— or—C(R^(a))₂NR^(a)SO₂C(R^(a))₂—; and/or

each R^(a) is, independently, hydrogen, halo, hydroxyl or C₁₋₄alkyl, orwherein two R^(a) groups, together with the carbon atom to which theyare attached, form C═O.

It is understood that any embodiment of the compounds of Formulas (I),(I-A), (I-B), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F),(II-G), (II-H), (II-I), (III), (III-A), (III-B), (III-C), (III-D),(III-E), (III-F), (III-G), (III-H), (III-I), (IV), (IV-A), (IV-B),(IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and (IV-I), as set forthabove, and any specific substituent set forth herein for a L, R¹, R²,R³, R⁴, R⁵, R^(a), W, X, Y¹, Y², or Z group in the compounds of Formulas(I), (I-A), (I-B), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F),(II-G), (II-H), (II-I), (III), (III-A), (III-B), (III-C), (III-D),(III-E), (III-F), (III-G), (III-H), (III-I), (IV), (IV-A), (IV-B),(IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and (IV-I), as set forthherein, may be independently combined with other embodiments and/orsubstituents of compounds of Formulas (I), (I-A), (I-B), (II), (II-A),(II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (III),(III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H),(III-I), (IV), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G),(IV-H), and (IV-I), to form embodiments of the inventions notspecifically set forth above. In addition, in the event that a list ofsubstituents is listed for any particular L, R¹, R², R³, R⁴, R⁵, R^(a),W, X, Y¹, Y², or Z in a particular embodiment and/or claim, it isunderstood that each individual substituent may be deleted from theparticular embodiment and/or claim and that the remaining list ofsubstituents will be considered to be within the scope of the invention.

As one of skill in the art will appreciate, compounds of Formulas (I),(I-A), (I-B), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F),(II-G), (II-H), (II-I), (III), (III-A), (III-B), (III-C), (III-D),(III-E), (III-F), (III-G), (III-H), (III-I), (IV), (IV-A), (IV-B),(IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and (IV-I) may be shownin several different ways. For example, the following compound may beshown as:

Pharmaceutical Compositions

For the purposes of administration, in certain embodiments, thecompounds described herein are administered as a raw chemical or areformulated as pharmaceutical compositions. Pharmaceutical compositionsof the present invention comprise a compound of Formulas (I), (I-A),(I-B), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G),(II-H), (II-I), (III), (III-A), (III-B), (III-C), (III-D), (III-E),(III-F), (III-G), (III-H), (III-I), (IV), (IV-A), (IV-B), (IV-C),(IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and (IV-I) I-A and apharmaceutically acceptable carrier, diluent or excipient. The compoundof Formulas (I), (I-A), (I-B), (II), (II-A), (II-B), (II-C), (II-D),(II-E), (II-F), (II-G), (II-H), (II-I), (II-I), (III-A), (III-B),(III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I), (IV),(IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and(IV-I) I-A is present in the composition in an amount which is effectiveto treat a particular disease or condition of interest. The activity ofcompounds of Formulas (I), (I-A), (I-B), (II), (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (III), (III-A), (III-B),(III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I), (IV),(IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and(IV-I) I-A can be determined by one skilled in the art, for example, asdescribed in the Examples below. Appropriate concentrations and dosagescan be readily determined by one skilled in the art.

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. Pharmaceutical compositions of the invention are formulatedso as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy.

Combination Therapy

In one embodiment, a method for treating or preventing an HIV infectionin a human having or at risk of having the infection is provided,comprising administering to the human a therapeutically effective amountof a compound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents. In one embodiment, a method for treating an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents.

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent or excipient are provided.

In one embodiment, combination pharmaceutical agents comprising acompound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with one or more (e.g., one, two, three, one ortwo, or one to three) additional therapeutic agents are provided.

In the above embodiments, the one or more additional therapeutic agentsmay be an anti-HIV agent. For example, in some embodiments, the one ormore additional therapeutic agent is selected from the group consistingof HIV protease inhibitors, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, entry inhibitors (e.g., CCR5inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachmentinhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidaseinhibitors, compounds that target the HIV capsid (“capsid inhibitors”;e.g., capsid polymerization inhibitors or capsid disrupting compoundssuch as those disclosed in WO 2013/006738 (Gilead Sciences), US2013/0165489 (University of Pennsylvania), and WO 2013/006792 (PharmaResources), pharmacokinetic enhancers, and other drugs for treating HIV,and combinations thereof.

In some embodiments, one or more the additional therapeutic agent isselected from the group consisting of HIV protease inhibitors, HIVnon-nucleoside inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,pharmacokinetic enhancers, and combinations thereof.

In some embodiments, the one or more additional therapeutic agent isselected from the group consisting of HIV protease inhibitors, HIVnon-nucleoside inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, and combinations thereof.

In further embodiments, the one or more additional therapeutic agent isselected from one or more of:

(1) HIV protease inhibitors selected from the group consisting ofamprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir,nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;

(2) HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase selected from the group consisting of capravirine,emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A,etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120,rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK-453061), RDEA806,KM023 and MK-1439;

(3) HIV nucleoside or nucleotide inhibitors of reverse transcriptaseselected from the group consisting of zidovudine, emtricitabine,didanosine, stavudine, zalcitabine, lamivudine, abacavir, abavavirsulfate, amdoxovir, elvucitabine, alovudine, MIV-210, ±-FTC, D-d4FC,emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754),KP-1461, GS-9131 (Gilead Sciences) and fosalvudine tidoxil (formerly HDP99.0003), tenofovir, tenofovir disoproxil fumarate, tenofoviralafenamide (Gilead Sciences), tenofovir alafenamide hemifumarate(Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovirdipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix);

(4) HIV integrase inhibitors selected from the group consisting ofcurcumin, derivatives of curcumin, chicoric acid, derivatives ofchicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, andL-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA011, elvitegravir, dolutegravir and GSK-744;

(5) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI)including, but not limited to, BI-224436, CX0516, CX05045, CX14442,compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO2012/003498 (Gilead Sciences) each of which is incorporated byreferences in its entirety herein;

(6) gp41 inhibitors selected from the group consisting of enfuvirtide,sifuvirtide, albuvirtide, FB006M, and TRI-1144;

(7) the CXCR4 inhibitor AMD-070;

(8) the entry inhibitor SP01A;

(9) the gp120 inhibitor BMS-488043;

(10) the G6PD and NADH-oxidase inhibitor immunitin;

(11) CCR5 inhibitors selected from the group consisting of aplaviroc,vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798(Pfizer), and CCR5mAb004;

(12) CD4 attachment inhibitors selected from the group consisting ofibalizumab (TMB-355) and BMS-068 (BMS-663068);

(13) pharmacokinetic enhancers selected from the group consisting ofcobicistat and SPI-452; and

(14) other drugs for treating HIV selected from the group consisting ofBAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1,PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, andPA-1050040 (PA-040), and combinations thereof.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The two, three, fouror more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, or they canbe selected from different classes of therapeutic agents. In a specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase and an HIV non-nucleosideinhibitor of reverse transcriptase. In another specific embodiment, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with an HIV nucleoside or nucleotide inhibitor ofreverse transcriptase, and an HIV protease inhibiting compound. In afurther embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, an HIV non-nucleosideinhibitor of reverse transcriptase, and an HIV protease inhibitingcompound. In an additional embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase, an HIVnon-nucleoside inhibitor of reverse transcriptase, and a pharmacokineticenhancer. In another embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with two HIVnucleoside or nucleotide inhibitor of reverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil fumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofoviralafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofoviralafenamide, and tenofovir alafenamide hemifumarate and a secondadditional therapeutic agent selected from the group consisting ofemtricitibine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, andtenofovir alafenamide hemifumarate and a second additional therapeuticagent, wherein the second additional therapeutic agent is emtricitibine.

In certain embodiments, when a compound disclosed herein is combinedwith one or more additional therapeutic agents as described above, thecomponents of the composition are administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments, a compound disclosed herein is administered withone or more additional therapeutic agents. Co-administration of acompound disclosed herein with one or more additional therapeutic agentsgenerally refers to simultaneous or sequential administration of acompound disclosed herein and one or more additional therapeutic agents,such that therapeutically effective amounts of the compound disclosedherein and one or more additional therapeutic agents are both present inthe body of the patient.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents, for example,administration of the compound disclosed herein within seconds, minutes,or hours of the administration of one or more additional therapeuticagents. For example, in some embodiments, a unit dose of a compounddisclosed herein is administered first, followed within seconds orminutes by administration of a unit dose of one or more additionaltherapeutic agents. Alternatively, in other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed by administration of a unit dose of a compound disclosed hereinwithin seconds or minutes. In some embodiments, a unit dose of acompound disclosed herein is administered first, followed, after aperiod of hours (e.g., 1-12 hours), by administration of a unit dose ofone or more additional therapeutic agents. In other embodiments, a unitdose of one or more additional therapeutic agents is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound disclosed herein.

The following Examples illustrate various methods of making compounds ofthis invention, i.e., compounds of Formula (I):

wherein L, R¹, R⁵, W, X, Y¹, Y², and Z are as defined above. It isunderstood that one skilled in the art may be able to make thesecompounds by similar methods or by combining other methods known to oneskilled in the art. It is also understood that one skilled in the artwould be able to make, in a similar manner as described below, othercompounds of Formulas (I), (I-A), (I-B), (II), (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (III), (III-A), (III-B),(III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I), (IV),(IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), and(IV-I) not specifically illustrated below by using the appropriatestarting components and modifying the parameters of the synthesis asneeded. In general, starting components may be obtained from sourcessuch as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, MatrixScientific, TCI, and Fluorochem USA, etc. or synthesized according tosources known to those skilled in the art (see, for example, AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure, 5th edition(Wiley, December 2000)) or prepared as described herein.

The following examples are provided for purposes of illustration, notlimitation.

EXAMPLES Representative Compounds Example 1 Preparation of Compound 1

Step 1

A 100-mL 1-neck round bottom flask was charged with reactant 1-A (2.0 g,8.8 mmol) in THF (20 mL). The reaction mixture was cooled to 0° C., andborane dimethyl sulfide (2 N in THF, 17.6 mL) was slowly added in. Thenthe reaction mixture was stirred at room temperature overnight. Themixture was cooled to 0° C. Methanol (8 mL) was added drop wise toquench the reaction. After concentration, the residue was purified bycolumn chromatography on silica gel using hexanes-ethyl acetate aseluents to afford 1-B.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₈H₁₉F₂N₂O₇: 214; found: 214.

Step 2

A 100-mL 1-neck round bottom flask was charged with reactant 1-B (1.5 g,7.0 mmol), triphenylphosphine (4.1 g, 15.6 mmol) and phthalimide (1.7 g,11.3 mmol) in THF (30 mL). Then the reaction mixture was cooled to 0° C.with stirring. DIAD (3.1 g, 15.6 mmol) was slowly added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.After concentration, the residue was purified by column chromatographyon silica gel using hexanes—ethyl acetate as eluents to afford 1-C.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₈H₁₉F₂N₂O₇: 343; found: 343.

Step 3

To a solution of reactant 1-C (2.3 g, 6.7 mmol) in EtOH (40 mL) wasadded hydrazine monohydrate (1.3 mL). The reaction mixture was heated to70° C. with stirring for 3 hours. After filtration to remove the solid,the filtrate was concentrated to afford compound 1-D.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₈H₁₉F₂N₂O₇: 213; found: 213.

Step 4

A 100-mL 1-neck round bottom flask was charged with reactant 1-D (0.3 g,1.4 mmol) and reactant 1-E (0.5 g, 1.4 mmol) in Ethanol (7 mL). Sodiumbicarbonate (0.24 g, 2.8 mmol) in water (7 mL) was added to the reactionmixture. Then the reaction mixture was stirred at room temperature forovernight. The mixture was diluted with ethyl acetate (50 mL) and washedwith water (×2). The aqueous fractions were extracted with ethyl acetate(×1), and the organic fractions were combined, dried (Na₂SO₄), andconcentrated. The crude 1-F was used for next step without furtherpurification.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₈H₁₉F₂N₂O₇: 541; found: 541.

Step 5

A 100-mL 1-neck round bottom flask was charged with reactant 1-F (0.75g, 1.4 mmol) in 4 N HCl in dioxane (8 mL). Then the reaction mixture wasstirred at room temperature for 1 hour. After concentration, 0.65 gintermediate was obtained. The intermediate and DBU (1.0 g, 6.8 mmol)were dissolved in toluene (10 mL). The reaction mixture was heated to110° C. with stirring for 1 hour. After concentration, the residue waspurified by column chromatography on silica gel using hexanes—ethylacetate as eluents to afford 1-G.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₈H₁₉F₂N₂O₇: 395; found: 395.

Step 6

A 100-mL 1-neck round bottom flask was charged with reactant 1-G (0.24g, 0.61 mmol) in THF (2 mL) and MeOH (2 mL). 1 N KOH (1.8 mL) was addedto the reaction mixture. Then the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was acidified by adding 1 NHCl (1.8 mL). After concentration, the residue was co-evaporated withtoluene (3×). The crude acid, 2,4-difluobenzylamine (0.17 g, 1.22 mmol),DIPEA (0.39 g, 3.04 mmol) and HATU (0.46 g, 1.22 mmol) were dissolved inDMF (10 mL). The reaction mixture was stirred at room temperature for 2hours. The mixture was diluted with ethyl acetate (100 mL) and washedwith sat NaHCO₃ (×2), sat NH₄Cl (×2) and dried (Na₂SO₄). Afterconcentration, the crude was purified by column chromatography on silicagel with hexane-ethyl acetate to afford compound 1-H.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₈H₁₉F₂N₂O₇: 492; found: 492.

Steps 7

A 50-mL 1-neck round bottom flask was charged with reactant 1-H (0.24 g,0.49 mmol) in TFA (3 mL). The reaction mixture was stirred at roomtemperature for 30 minutes. After concentration, the crude was purifiedby column chromatography on silica gel with ethyl acetate-methanol toafford compound 1.

¹H NMR (400 MHz, Chloroform-d) δ 12.63 (s, 1H), 10.43 (s, 1H), 8.30 (s,1H), 7.36 (d, J=10.1 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 4.64 (d, J=5.3 Hz,2H), 4.40 (s, 2H), 3.72 (d, J=3.7 Hz, 2H), 3.11 (d, J=4.7 Hz, 1H), 2.15(d, J=5.4 Hz, 2H), 1.71 (d, J=4.7 Hz, 2H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −112.31-112.36 (m, 1F), −114.75 (m,1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 402. found: 402.

Example 2 Preparation of Compound 2

Step 1 and Step 2

To a slurry of LAH (1893 mg, 44.88 mmol) in THF (40 mL) was addedcompound 2-A (894 mg, 5.315 mmol) at room temperature and the resultingmixture was refluxed. After 5 hours, the mixture was cooled to 0° C. andadditional LAH (1103 mg, 29.06 mmol) and THF (40 mL) were added and theresulting mixture was refluxed for 16 hours. The mixture was stirred at0° C. as water (3 mL), 15% NaOH (3 mL), and water (9 mL) were slowlyadded in the sequence. After stirring for 2 hours at 0° C., the mixturewas filtered and the filtrate was concentrated to a small amount,diluted with ethyl acetate, and dried (MgSO₄) and concentrated.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₈H₁₇N₂: 141.14; found: 141.1.

The residue (crude 2-B), compound 1-E (496 mg, 1.432 mmol), and NaHCO₃(326 mg, 3.881 mmol) in EtOH (˜6 mL) and water (˜4 mL) was stirred atroom temperature for 15 hours. The mixture was concentrated,coevaporated with toluene (×2), and dried in vacuum for 30 minutes. Theresidue was dissolved in 4 N HCl/dioxane (10 mL) and the suspension wasstirred at room temperature for 30 minutes. The resulting suspension wasconcentrated and dried in vacuum for 30 minutes.

To the crude residue in the above reaction, was added DBU (1 mL, 6.687mmol) and toluene (10 mL). The resulting slurry was stirred at 110° C.bath for 1 hour. The reaction mixture was concentrated, and the residuewas diluted with ethyl acetate before washing with water (×2). After theaqueous fractions were extracted with ethyl acetate (×1), the twoorganic fractions were combined, dried (Na₂SO₄), and concentrated. Theconcentrated residue was purified by column chromatography on silica gelusing ethyl acetate-20% MeOH in ethyl acetate as eluent to get compound2-C.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₄H₂₇N₂O₅: 423.19; found: 423.2.

Step 3

A mixture of compound 2-C (32 mg, 0.076 mmol) in THF (1 mL) and MeOH (1mL) was stirred at room temperature as 1 N KOH (1 mL) was added. After15 minutes, the reaction mixture was concentrated and diluted with waterbefore washing with ether (×1). The aqueous fraction was acidified with1 N HCl (˜1.1 mL), and extracted with CH₂Cl₂ (×2). The combined extractswere dried (Na₂SO₄) and used for the next reaction.

To the solution of the crude acid were added 2,4-difluorobenzylamine (26mg, 0.182 mmol) and HATU (56 mg, 0.147 mmol) at room temperaturefollowed by DIPEA (0.2 mL, 1.148 mmol). After 45 minutes at roomtemperature, the mixture was washed with saturated NH₄Cl (×1) andsaturated NaHCO₃ (×1). After the aqueous fractions were extracted withCH₂Cl₂ (×1), the organic fractions were combined, dried (Na₂SO₄), andconcentrated. The residue was purified by column chromatography onsilica gel using ethyl acetate-20% MeOH/ethyl acetate as eluents to getcompound 2-D.

¹H NMR (400 MHz, Chloroform-d) δ10.49 (t, J=6.1 Hz, 1H), 8.31 (s, 1H),7.60 (dt, J=6.5, 1.5 Hz, 2H), 7.44-7.27 (m, 4H), 6.87-6.75 (m, 2H), 5.28(s, 2H), 4.64 (d, J=6.0 Hz, 2H), 3.88 (s, 2H), 3.66-3.57 (m, 2H),2.15-2.07 (m, 1H), 1.85-1.56 (m, 8H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −112.20 (p, J=7.7 Hz), −114.73 (q,J=8.6 Hz).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₉H₂₈F₂N₃O₄: 520.20; found:520.2.

Step 4

Compound 2-D (26 mg, 0.050 mmol) was dissolved in TFA (2 mL) and stirredat room temperature and concentrated. The residue was purified bypreparative HPLC and the collected fraction was freeze-dried to getcompound 2.

¹H NMR (400 MHz, Chloroform-d) δ 12.60 (s, 1H), 10.48 (s, 1H), 8.26 (s,1H), 7.36 (d, J=7.6 Hz, 1H), 6.87-6.73 (m, 2H), 4.64 (d, J=5.9 Hz, 2H),3.90 (s, 2H), 3.69 (d, J=2.4 Hz, 2H), 2.20 (s, 1H), 2.03-1.89 (m, 2H),1.78 (d, J=26.7 Hz, 7H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −112.36 (m, 1F), −114.73 (m, 1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₂F₂N₃O₄: 430.16; found:430.2.

Example 3 Preparation of Compound 3

Step 1

A solution of compound 3-A (2.562 g, 10.62 mmol) in THF (26 mL) wasstirred at 0° C. as 2.0 M borane dimethyl sulfide in THF (21.4 mL) wasadded. The reaction was stirred at room temperature. After 21 hours, thereaction mixture was cooled to 0° C. before addition of methanol toquench the reaction. The reaction mixture was concentrated and theresidue was purified by column chromatography on silica gel usinghexanes—ethyl acetate as eluent to get compound 3-B.

¹H NMR (400 MHz, Chloroform-d) δ 4.24 (t, J=4.8 Hz, 1H), 3.90 (s, 2H),1.93-1.70 (m, 4H), 1.49-1.36 (m, 5H), 1.45 (s, 9H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₂H₂₂NO₃: 228.16; found: 227.8.

Step 2

A solution of compound 3-B (1106 mg, 4.866 mmol) and NEt₃ (0.90 mL,6.457 mmol) in CH₂Cl₂ (11 mL) was stirred at 0° C. as MsCl (0.42 mL,5.426 mmol) was added. After 45 minutes at 0° C., the mixture wasdiluted with ethyl acetate and washed with water (×2). The aqueousfractions were extracted with ethyl acetate (×1), and the organicfractions were combined, dried (Na₂SO₄), and concentrated. The residuewas purified by column chromatography on silica gel using hexanes—ethylacetate as eluents to get compound 3-C.

¹H NMR (400 MHz, Chloroform-d) δ 4.84 (s, 2H), 4.29 (p, J=2.4 Hz, 1H),3.07 (s, 3H), 1.90-1.73 (m, 4H), 1.72-1.57 (m, 2H), 1.51-1.45 (m, 2H),1.45 (s, 9H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₃H₂₄NO₅S: 306.14; found: 305.6.

Step 3

To a solution of compound 3-C (1398 mg, 4.578 mmol) in DMF (7 mL) wasadded sodium azide (1494 mg, 22.98 mmol). The mixture was stirred at110° C. for 8 hours. The reaction mixture was diluted with 5% LiClsolution and the product was extracted with ethyl acetate (×2). Afterthe aqueous fractions were extracted with ethyl acetate (×1), the twoorganic fractions were combined, dried (Na₂SO₄), and concentrated. Theresidue was purified by column chromatography on silica gel usinghexanes—ethyl acetate as eluents to get compound 3-D.

¹H NMR (400 MHz, Chloroform-d) δ 4.35-4.22 (m, 1H), 3.96 (s, 2H),1.91-1.71 (m, 4H), 1.64-1.49 (m, 2H), 1.46 (s, 9H), 1.48-1.41 (m, 2H).

Step 4

To a solution of compound 3-D (227 mg, 0.900 mmol) in EtOH (3 mL) wasadded 10% Pd/C (29 mg) and the mixture was stirred under H₂ atmospherefor 30 minutes. The mixture was filtered through celite pad andconcentrated. The crude compound 3-E was used for the next reaction.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₂H₂₃N₂O₂: 227.18; found: 226.8.

Step 5

A mixture of the crude compound 3-E, compound 1-E (328 mg, 0.947 mmol)and NaHCO₃ (152 mg, 1.812 mmol) in water (3 mL) and EtOH (9 mL) wasstirred at room temperature for 18 hours. The mixture was concentratedto ˜½ volume, diluted with water, and the product was extracted (×2).The organic fractions were washed with water (×1), combined, dried(Na₂SO₄), and concentrated. The residue was used for the next reaction.

To a solution of the above residue in CH₂Cl₂ (2 mL) was added 4 N HCl indioxane (6 mL) at room temperature. After 2 hours, additional 4 N HCl (3mL) was added. After 2.5 hours, the mixture was concentrated andco-evaporated with toluene (×1). The residue was used for the nextreaction.

A mixture of the above residue and DBU (0.68 mL, 4.547 mmol) in toluene(10 mL) was stirred at 110° C. bath. After 3 hours at 110° C., thereaction mixture was dissolved in CH₂Cl₂ and concentrated. The residuewas purified by column chromatography on silica gel using ethylacetate-20% MeOH/ethyl acetate as eluents to get compound 3-G.

¹H NMR (400 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.73-7.63 (m, 2H),7.38-7.21 (m, 3H), 5.29 (s, 2H), 4.76 (t, J=4.8 Hz, 1H), 4.44-4.34 (q,J=7.2 Hz, 2H), 4.29 (s, 2H), 1.95 (m, 2H), 1.82-1.56 (m, 6H), 1.45-1.35(t, J=7.2 Hz, 3H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₂₅N₂O₅: 409.18; found: 409.3.

Step 6

A mixture of compound 3-G (233 mg, 0.570 mmol) in THF (3 mL) and MeOH (3mL) was stirred at room temperature as 1 N KOH (3 mL) was added. After30 minutes at room temperature, the reaction mixture was concentratedand diluted with water before washing with ether (×1). The aqueousfraction was acidified with 1 N HCl (˜3.3 mL), and extracted with ethylacetate (×2). The extracts were washed with brine (×1), combined, dried(Na₂SO₄), and concentrated to get 207 mg (95%) of the crude acid. Thecrude acid was used for the next reaction.

A mixture of the crude acid (207 mg, 0.544 mmol),2,4-difluorobenzylamine (100 mg, 0.699 mmol), and HATU (259 mg, 0.681mmol) in CH₂Cl₂ (5 mL) was stirred at room temperature as DIPEA (0.68mL, 3.904 mmol) was added. After 45 minutes, the mixture was dilutedwith ethyl acetate, washed with saturated NH₄Cl (×1) and saturatedNaHCO₃ (×1). After the aqueous fractions were extracted with ethylacetate (×1), the organic fractions were combined, dried (Na₂SO₄), andconcentrated. The residue was purified by column chromatography onsilica gel using ethyl acetate-20% MeOH/ethyl acetate as eluents to getcompound 3-H.

¹H NMR (400 MHz, Chloroform-d) δ 10.41 (s, 1H), 8.40 (s, 1H), 7.63-7.57(m, 2H), 7.41-7.27 (m, 4H), 6.87-6.76 (m, 2H), 5.27 (s, 2H), 4.81 (t,J=4.8 Hz, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.37 (s, 2H), 2.03-1.92 (m, 2H),1.86-1.75 (m, 2H), 1.74-1.62 (m, 4H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −112.16 (q, J=8.0 Hz, 1F), −114.71 (q,J=8.5 Hz, 1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₈H₂₆F₂N₃O₄: 506.19; found:506.2.

Step 7

Compound 3-H (246 mg, 0.487 mmol) was dissolved and stirred in TFA (5mL) at room temperature. After 30 minutes, the solution was concentratedand the residue was purified by column chromatography on silica gelusing CH₂Cl₂-20% MeOH in CH₂Cl₂ as eluents. The collected fractions wereconcentrated and the residue was dissolved in MeCN (1 mL) at roomtemperature and diluted with MeOH (4 mL) which made solids. Theresulting mixture was stored in 0° C. bath for 20 minutes and the solidswere filtered, washed with MeOH, and dried in vacuum to get compound 3.

¹H NMR (400 MHz, Chloroform-d) δ 12.58 (s, 1H), 10.43 (s, 1H), 8.36 (s,1H), 7.44-7.30 (m, 1H), 6.90-6.72 (m, 2H), 4.82 (t, J=4.7 Hz, 1H),4.71-4.59 (d, J=5.6 Hz, 2H), 4.39 (s, 2H), 2.06-2.01 (m, 2H), 1.91-1.84(m, 2H), 1.81-1.71 (m, 4H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −112.34 (m, 1F), −114.73 (m, 1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₁₉F₂N₃O₄: 416.14; found:416.20.

Example 4 Preparation of Compound 4

Step 1

The mixture of compound 1-E (320 mg, 0.924 mmol), compound 4-A(Tetrahedron: Asymmetry 2006, 17, 252-258; 220 mg, 0.915 mmol), andNaHCO₃ (156 mg, 1.857 mmol) in water (3 mL) and EtOH (3 mL) was stirredat room temperature. After 2 hours, the reaction mixture was dilutedwith water and extracted with ethyl acetate (twice). After the extractswere washed with water, the organic fractions were combined, dried(Na₂SO₄), and concentrated. The residue was dried under vacuum and usedfor the next reaction.

To a solution of the residue in CH₂Cl₂ (2 mL) was added 4 N HCl indioxane (4 mL) at room temperature. After 1.5 hours, the solution wasconcentrated and dried under vacuum for 1 hour. A suspension of theresidue and DBU (0.55 mL, 3.678 mmol) in toluene (5 mL) was stirred at110° C. bath for 30 min. After the mixture was concentrated, the residuewas purified by column chromatography on silica gel using ethylacetate-20% MeOH/ethyl acetate as eluents to obtain compound 4-B.

¹H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.71-7.63 (m, 2H), 7.33(ddt, J=8.0, 6.6, 1.1 Hz, 2H), 7.30-7.26 (m, 1H), 5.54 (d, J=9.9 Hz,1H), 5.18 (d, J=9.9 Hz, 1H), 4.40 (qd, J=7.1, 2.3 Hz, 2H), 4.03-3.92 (m,2H), 3.78-3.67 (m, 1H), 3.52 (d, J=12.2 Hz, 1H), 2.66 (d, J=5.1 Hz, 1H),1.82 (d, J=2.6 Hz, 2H), 1.75-1.43 (m, 6H), 1.40 (t, J=7.1 Hz, 3H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₄H₂₇N₂O₅: 423.19; found: 423.3.

Step 2

A mixture of compound 4-B (70 mg, 0.166 mmol) in THF (2 mL) and MeOH (2mL) was stirred at room temperature as 1 N KOH (0.35 mL) was added.After 2.25 hours, the reaction mixture was concentrated, acidified with1 N HCl (˜0.4 mL), and diluted with brine before extraction with CH₂Cl₂(thrice). The combined extracts was dried (Na₂SO₄) and concentrated. Theresidual crude acid was used for the next reaction.

A mixture of the crude acid, 2,4-difluorobenzylamine (33 mg, 0.231mmol), and HATU (93 mg, 0.245 mmol) in CH₂Cl₂ (3 mL) was stirred at roomtemperature as DIPEA (0.20 mL, 1.148 mmol) was added. After 30 min, thereaction mixture was diluted with ethyl acetate, and washed withsaturated NH₄Cl, water, saturated NaHCO₃, and brine. After the aqueousfractions were extracted with ethyl acetate, the two organic fractionswere combined, dried (Na₂SO₄) and concentrated. The residue was purifiedby column chromatography on silica gel using ethyl acetate-20%MeOH/ethyl acetate as eluents to obtain compound 4-C.

¹H NMR (400 MHz, Chloroform-d) δ 10.61-10.40 (m, 1H), 8.37 (s, 1H),7.66-7.54 (m, 2H), 7.44-7.22 (m, 4H), 6.89-6.74 (m, 2H), 5.42 (d, J=10.0Hz, 1H), 5.20 (d, J=9.9 Hz, 1H), 4.73-4.54 (m, 2H), 4.11-3.97 (m, 2H),3.72 (dd, J=12.4, 5.4 Hz, 1H), 3.51 (d, J=12.3 Hz, 1H), 2.65 (dt, J=5.7,3.1 Hz, 1H), 1.88-1.77 (m, 2H), 1.77-1.31 (m, 6H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −112.19 (p, J=8.0 Hz, 1F), −114.73 (q,J=8.5 Hz, 1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₉H₂₈F₂N₃O₄: 520.20; found:520.3.

Step 3

Compound 4-C (76 mg, 0.146 mmol) was dissolved in TFA (1 mL) and stirredat room temperature. After 30 min, the solution was concentrated and theresidue was purified by column chromatography on silica gel usingCH₂Cl₂-20% MeOH in CH₂Cl₂ as eluents to obtain compound 4.

¹H NMR (400 MHz, Chloroform-d) δ 10.50 (t, J=6.0 Hz, 1H), 8.39 (s, 1H),7.34 (td, J=8.7, 6.5 Hz, 1H), 6.86-6.71 (m, 2H), 4.68-4.53 (m, 2H), 4.20(d, J=12.8 Hz, 1H), 4.06 (d, J=12.8 Hz, 1H), 3.73-3.56 (m, 2H), 2.72 (t,J=3.9 Hz, 1H), 1.99-1.82 (m, 2H), 1.83-1.67 (m, 3H), 1.62 (td, J=12.7,4.5 Hz, 1H), 1.56-1.39 (m, 2H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −112.16 (p, J=7.7 Hz, 1F), −114.77 (q,J=8.5 Hz, 1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₂F₂N₃O₄: 430.16; found:430.3.

Example 5 Preparation of Compound 5

Step 1

A mixture of compound 4-B (70 mg, 0.166 mmol) in THF (2 mL) and MeOH (2mL) was stirred at room temperature as 1 N KOH (0.35 mL) was added.After 2.25 hours, the reaction mixture was concentrated, acidified with1 N HCl (˜0.4 mL), and diluted with brine before extraction with CH₂Cl₂(thrice). The combined extracts was dried (Na₂SO₄) and concentrated. Theresidual crude acid was used for the next reaction.

A mixture of the crude acid, 2,4,6-trifluorobenzylamine (41 mg, 0.254mmol), and HATU (97 mg, 0.255 mmol) in CH₂Cl₂ (3 mL) was stirred at roomtemperature as DIPEA (0.20 mL, 1.148 mmol) was added. After ˜30 min, thereaction mixture was diluted with ethyl acetate, and washed withsaturated NH₄Cl, water, saturated NaHCO₃, and brine. After the aqueousfractions were extracted with ethyl acetate, two organic fractions werecombined, dried (Na₂SO₄) and concentrated. The residue was purified bycolumn chromatography on silica gel using ethyl acetate-20% MeOH/ethylacetate as eluents to obtain compound 5-A.

¹H NMR (400 MHz, Chloroform-d) δ 10.40 (t, J=5.7 Hz, 1H), 8.35 (s, 1H),7.64-7.53 (m, 2H), 7.35-7.23 (m, 3H), 6.74-6.57 (m, 2H), 5.41 (d, J=10.0Hz, 1H), 5.19 (d, J=10.0 Hz, 1H), 4.76-4.54 (m, 2H), 4.03 (d, J=2.5 Hz,2H), 3.76-3.63 (m, 1H), 3.50 (d, J=12.3 Hz, 1H), 2.64 (dq, J=5.0, 2.4Hz, 1H), 1.87-1.76 (m, 2H), 1.76-1.30 (m, 6H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −109.10 (tt, J=8.8, 6.3 Hz, 1F),−111.87 (t, J=7.0 Hz, 2F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₉H₂₇F₃N₃O₄: 538.20; found:538.3.

Step 2

Compound 5-A (78 mg, 0.145 mmol) was dissolved in TFA (1 mL) and stirredat room temperature. After 30 min, the solution was concentrated and theresidue was purified by column chromatography on silica gel usingCH₂Cl₂-20% MeOH in CH₂Cl₂ as eluents to obtain compound 5.

¹H NMR (400 MHz, Chloroform-d) δ 10.42 (s, 1H), 8.31 (s, 1H), 6.65 (dd,J=8.7, 7.5 Hz, 2H), 4.66 (d, J=5.8 Hz, 2H), 4.13-3.96 (m, 2H), 3.72-3.60(m, 2H), 2.73 (d, J=4.9 Hz, 1H), 1.92 (s, 2H), 1.84-1.41 (m, 6H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −109.18 (tt, J=8.7, 6.3 Hz, 1F),−111.98 (t, J=6.9 Hz, 2F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₁F₃N₃O₄: 448.15; found:448.3.

Example 6 Preparation of Compound 6

Step 1

The mixture of compound 1-E (970 mg, 2.801 mmol), compound 6-A(Tetrahedron: Asymmetry 2006, 17, 252-258; 778 mg, 2.811 mmol), andNaHCO₃ (472 mg, 1.857 mmol) in water (5 mL) and EtOH (5 mL) was stirredat room temperature. After 2 hours, the reaction mixture was dilutedwith water and extracted with ethyl acetate (twice). After the extractswere washed with water, the organic fractions were combined, dried(Na₂SO₄), and concentrated. The residue was dried under vacuum and usedfor the next reaction.

To a solution of the residue in CH₂Cl₂ (3 mL) was added 4 N HCl indioxane (7 mL) at room temperature. After 2 hours, the solution wasconcentrated and co-evaporated with toluene (×1). A suspension of theresidue and DBU (1.75 mL, 11.70 mmol) in toluene (17.5 mL) was stirredat 110° C. bath for 1 hour. After the mixture was concentrated, theresidue was purified by column chromatography on silica gel using ethylacetate-20% MeOH/ethyl acetate as eluents to obtain compound 6-B.

¹H NMR (400 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.71-7.64 (m, 2H),7.37-7.27 (m, 3H), 5.54 (d, J=9.9 Hz, 1H), 5.18 (d, J=9.9 Hz, 1H), 4.41(qd, J=7.2, 2.4 Hz, 2H), 3.98 (d, J=1.3 Hz, 2H), 3.73 (dd, J=12.1, 5.6Hz, 1H), 3.52 (d, J=12.3 Hz, 1H), 2.65 (s, 1H), 1.82 (d, J=2.7 Hz, 2H),1.75-1.43 (m, 6H), 1.40 (t, J=7.1 Hz, 3H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₄H₂₇N₂O₅: 423.19; found: 423.3.

Step 2 and Step 3

A mixture of compound 6-B (962 mg, 2.277 mmol) in THF (5 mL) and MeOH (5mL) was stirred at room temperature as 1 N KOH (4.85 mL) was added.After 1 hour, the reaction mixture was concentrated to ˜5 mL, acidifiedwith 1 N HCl (˜5 mL), and diluted with brine before extraction withCH₂Cl₂ (50 mL×2). The combined extracts was dried (Na₂SO₄) andconcentrated to provide compound 6-C.

A mixture of compound 6-C (102 mg, 0.259 mmol), 2,4-difluorobenzylamine(58 mg, 0.405 mmol), and HATU (152 mg, 0.400 mmol) in CH₂Cl₂ (5 mL) wasstirred at room temperature as DIPEA (0.35 mL, 2.009 mmol) was added.After 1 hour, the reaction mixture was diluted with ethyl acetate, andwashed with saturated NH₄Cl, water, saturated NaHCO₃, and brine. Afterthe aqueous fractions were extracted with ethyl acetate, two organicfractions were combined, dried (Na₂SO₄) and concentrated. The residuewas purified by column chromatography on silica gel using ethylacetate-20% MeOH/ethyl acetate as eluents to obtain compound 6-D.

¹H NMR (400 MHz, Chloroform-d) δ 10.50 (t, J=6.0 Hz, 1H), 8.38 (s, 1H),7.66-7.52 (m, 2H), 7.42-7.20 (m, 4H), 6.90-6.72 (m, 2H), 5.41 (d, J=10.0Hz, 1H), 5.20 (d, J=10.0 Hz, 1H), 4.74-4.53 (m, 2H), 4.05 (q, J=12.9 Hz,2H), 3.71 (dd, J=12.3, 5.4 Hz, 1H), 3.50 (d, J=12.3 Hz, 1H), 2.64 (dt,J=5.7, 2.9 Hz, 1H), 1.86-1.78 (m, 2H), 1.78-1.30 (m, 6H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −112.20 (p, J=7.6 Hz, 1F), −114.76 (q,J=8.6 Hz, 1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₉H₂₈F₂N₃O₄: 520.20; found:520.3.

Step 4

Compound 6-D (122 mg, 0.235 mmol) was dissolved in TFA (1.5 mL) andstirred at room temperature. After 30 min, the solution was concentratedand the residue was dissolved in CH₂Cl₂ before washing with 0.1 N HCl.After the aqueous fraction was extracted with CH₂Cl₂ (twice), theorganic fractions were combined, dried (Na₂SO₄), and concentrated. Theresidue was purified by column chromatography on silica gel usingCH₂Cl₂-20% MeOH in CH₂Cl₂ as eluents to obtain compound 6.

¹H NMR (400 MHz, Chloroform-d) δ 12.16 (s, 1H), 10.46 (s, 1H), 8.30 (s,1H), 7.36 (td, J=8.7, 6.3 Hz, 1H), 6.88-6.70 (m, 2H), 4.64 (d, J=6.0 Hz,2H), 4.06 (q, J=12.8 Hz, 2H), 3.75-3.62 (m, 2H), 2.74 (s, 1H), 1.93 (d,J=2.6 Hz, 2H), 1.87-1.70 (m, 3H), 1.70-1.42 (m, 3H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −112.40 (p, J=7.7 Hz, 1F), −114.76 (q,J=8.6 Hz, 1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₂F₂N₃O₄: 430.16; found:430.2.

Example 7 Preparation of Compound 7

Step 1

A mixture of compound 6-C (266 mg, 0.674 mmol),2,4,6-trifluorobenzylamine (150 mg, 0.931 mmol), and HATU (390 mg, 1.026mmol) in CH₂Cl₂ (10 mL) was stirred at room temperature as DIPEA (0.82mL, 4.708 mmol) was added. After 1 hour, the reaction mixture wasdiluted with ethyl acetate, and washed with saturated NH₄Cl, water,saturated NaHCO₃, and water. After the aqueous fractions were extractedwith ethyl acetate, two organic fractions were combined, dried (Na₂SO₄)and concentrated. The residue was purified by column chromatography onsilica gel using ethyl acetate-20% MeOH/ethyl acetate as eluents toobtain compound 7-A.

¹H NMR (400 MHz, Chloroform-d) δ 10.40 (t, J=5.9 Hz, 1H), 8.34 (s, 1H),7.65-7.51 (m, 2H), 7.38-7.20 (m, 3H), 6.74-6.58 (m, 2H), 5.41 (d, J=10.0Hz, 1H), 5.18 (d, J=10.0 Hz, 1H), 4.66 (qd, J=14.5, 5.8 Hz, 2H), 4.03(s, 2H), 3.71 (dd, J=12.4, 5.5 Hz, 1H), 3.50 (d, J=12.3 Hz, 1H), 2.64(dt, J=6.0, 3.2 Hz, 1H), 1.88-1.77 (m, 2H), 1.77-1.51 (m, 3H), 1.40 (m,3H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −109.12 (ddd, J=15.2, 8.9, 6.4 Hz,1F), −111.87 (t, J=7.0 Hz, 2F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₉H₂₇F₃N₃O₄: 538.20; found:538.3.

Step 2

Compound 7-A (266 mg, 0.495 mmol) was dissolved in TFA (3 mL) andstirred at room temperature. After 20 min, the solution was concentratedand the residue was dissolved in CH₂Cl₂ before washing with 0.1 N HCl.After the aqueous fraction was extracted with CH₂Cl₂ (twice), theorganic fractions were combined, dried (Na₂SO₄), and concentrated. Theresidue was purified by column chromatography on silica gel usingCH₂Cl₂-20% MeOH in CH₂Cl₂ as eluents to obtain compound 7. The obtainedproduct was further purified by trituration in methanol (1.5 mL) at roomtemperature for 1 hour and then 0° C. for 1 hour. The solids werefiltered, washed with methanol, and dried under vacuum overnight.

¹H NMR (400 MHz, Chloroform-d) δ 12.11 (s, 1H), 10.39 (t, J=5.9 Hz, 1H),8.28 (s, 1H), 6.74-6.57 (m, 2H), 4.73-4.58 (m, 2H), 4.12-3.97 (m, 2H),3.73-3.61 (m, 2H), 2.73 (s, 1H), 1.98-1.85 (m, 2H), 1.85-1.69 (m, 3H),1.69-1.42 (m, 3H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −109.26 (tt, J=8.9, 6.3 Hz, 1F),−111.99 (t, J=6.9 Hz, 2F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₁F₃N₃O₄: 448.15; found:448.3.

Example 8 Preparation of Compound 8

Step 1

A mixture of compound 6-C (151 mg, 0.383 mmol),3-chloro-2-fluorobenzylamine (91 mg, 0.570 mmol), and HATU (239 mg,0.629 mmol) in CH₂Cl₂ (5 mL) was stirred at room temperature as DIPEA(0.5 mL, 2.871 mmol) was added. After 1 hour, the reaction mixture wasdiluted with ethyl acetate, and washed with saturated NH₄Cl (twice),saturated NaHCO₃ (twice), and water. After the aqueous fractions wereextracted with ethyl acetate, the two organic fractions were combined,dried (Na₂SO₄) and concentrated. The residue was purified by columnchromatography on silica gel using ethyl acetate-20% MeOH/ethyl acetateas eluents to obtain compound 8-A.

¹H NMR (400 MHz, Chloroform-d) δ 10.57 (t, J=6.1 Hz, 1H), 8.40 (s, 1H),7.67-7.51 (m, 2H), 7.41-7.15 (m, 5H), 7.03 (td, J=7.9, 1.2 Hz, 1H), 5.42(d, J=10.0 Hz, 1H), 5.20 (d, J=10.0 Hz, 1H), 4.80-4.56 (m, 2H),4.16-4.06 (m, 2H), 4.01 (d, J=12.8 Hz, 1H), 3.71 (dd, J=12.4, 5.3 Hz,1H), 3.51 (d, J=12.3 Hz, 1H), 2.64 (s, 1H), 1.74-1.29 (m, 7H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −120.95 (t, J=6.9 Hz). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₂₉H₂₈ClFN₃O₄: 536.18; found: 536.2.

Step 2

Compound 8-A (73 mg, 0.136 mmol) was dissolved in TFA (3 mL) and stirredat room temperature. After 1 hour, the solution was concentrated and theresidue was dissolved in CH₂Cl₂ before washing with 0.1 N HCl. After theaqueous fraction was extracted with CH₂Cl₂ (twice), the organicfractions were combined, dried (Na₂SO₄), and concentrated. The residuewas purified by column chromatography on silica gel using CH₂Cl₂-20%MeOH in CH₂Cl₂ as eluents to obtain compound 8. The obtained product wasfurther purified by trituration in methanol (1 mL) at 0° C. for 1 hour.The solids were filtered, washed with methanol, and dried in vacuumovernight.

¹H NMR (400 MHz, Chloroform-d) δ 12.18 (s, 1H), 10.51 (s, 1H), 8.31 (s,1H), 7.32-7.26 (m, 2H), 7.06-6.98 (m, 1H), 4.71 (d, J=5.3 Hz, 2H),4.16-3.97 (m, 2H), 3.67 (d, J=5.0 Hz, 2H), 2.74 (d, J=4.9 Hz, 1H), 1.93(d, J=2.5 Hz, 2H), 1.87-1.70 (m, 3H), 1.70-1.58 (m, 1H), 1.58-1.43 (m,2H).

¹⁹F NMR (376 MHz, Chloroform-d) δ −120.94 (s).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₂ClFN₃O₄: 446.13; found:446.3.

Example 9 Preparation of Compound 9

Step 1

A flask containing DMSO (22 mL) was stirred in a water bath (˜18° C.) assmall portions of NaH (60%, 1.235 g, 30.88 mmol) was added slowly whilethe inner temperature of the mixture was maintained below 20° C. Afteraddition, Me₃SOI (6.79 g, 30.85 mmol) was added portionwise while thetemperature was kept below 20° C. After addition, the mixture wasstirred at the water bath (˜16˜18° C.) for 45 min. To the mixture wasadded a solution of compound 9-A (3.15 mL, 27.77 mmol) in DMSO (3.95 mL)dropwise. The resulting mixture was stirred at room temperature for 30min and then at 50° C. for 2 hours. The reaction mixture was poured to60 g of ice and the resulting mixture was transferred to a separatoryfunnel before the product was extracted with ether (˜50-70 mL twice).The extracts were washed with water, combined, dried (MgSO₄), andconcentrated. The residue was purified by column chromatography onsilica gel using hexanes—ethyl acetate as eluents. Collected fractionswere concentrated to a small volume at ˜20° C. bath by rotorvap toprovide compound 9-B.

¹H NMR (400 MHz, Chloroform-d) δ 2.35-2.23 (m, 1H), 2.08-1.89 (m, 2H),1.78-1.66 (m, 2H), 1.60 (qd, J=8.7, 7.8, 4.8 Hz, 2H), 1.40 (t, J=4.8 Hz,1H), 1.21 (s, 3H), 0.91 (dd, J=10.0, 5.1 Hz, 1H).

Step 2

A mixture of compound 9-B (3.824 g, 54% purity, 16.57 mmol) and pyridineHCl (7.680 g, 66.46 mmol) in acetonitrile (40 mL) was refluxed at 90° C.for 24 hours. The reaction mixture was diluted with water (150 mL) andthe product was extracted with ether (˜80 mL×3). The extracts werewashed with water, combined, dried (MgSO₄), and concentrated. Theresidue was purified by column chromatography on silica gel usinghexanes—ethyl acetate as eluents. Product containing fractions werecombined and concentrated by rotorvap to provide compound 9-C.

¹H NMR (400 MHz, Chloroform-d) δ 3.38 (s, 2H), 2.39 (d, J=13.9 Hz, 1H),2.30 (dddd, J=14.7, 13.4, 7.8, 4.7 Hz, 2H), 2.17 (dt, J=13.8, 1.7 Hz,1H), 2.01-1.79 (m, 3H), 1.58 (dd, J=10.0, 5.1 Hz, 1H), 1.03 (s, 3H).

Step 3

A solution of gamma-chloroketone compound 9-C (3.666 g, 56% purity,12.78 mmol), (R)-1-phenylethylamine (1.72 mL, 13.46 mmol), and acetonecyanohydrine (3.5 mL, 38.25 mmol) in MeOH (11 mL) was refluxed in 75° C.bath. After 41.5 hours, the reaction mixture was diluted with CH₂Cl₂ andwashed with aq. NaHCO₃ and water. After the aqueous fractions wereextracted with CH₂Cl₂, the organic fractions were combined, dried(MgSO₄), and concentrated. The residue was purified by columnchromatography on silica gel using hexane-ethyl acetate as eluents toobtain compounds 9-D and 9-D′.

¹H NMR (400 MHz, Chloroform-d) δ 7.34 (m, 4H), 7.28-7.19 (m, 1H), 4.10(q, J=6.7 Hz, 1H), 2.80-2.62 (m, 1H), 2.37 (t, J=9.8 Hz, 1H), 2.28 (dd,J=21.2, 10.4 Hz, 2H), 1.78 (q, J=10.0, 7.9 Hz, 3H), 1.70-1.47 (m, J=5.8,4.4 Hz, 4H), 1.46-1.29 (m, 2H), 0.96 (s, 3H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₇H₂₃N₂: 255.19; found: 254.9.

Step 4

A mixture of compound 9-D (229 mg, 0.900 mmol) and 20% Pd(OH)₂/C (118mg) in EtOH (7 mL) and 4 N HCl in dioxane (0.9 mL) was stirred under H₂atmosphere. After 3 hours, additional 20% Pd(OH)₂/C (55 mg) was added.After 2.5 hours, additional 20% Pd(OH)₂/C (61 mg) was added. After 2.5hours, the reaction mixture was filtered and the filtrate wasconcentrated to provide compound 9-E.

¹H NMR (400 MHz, DMSO-d₆) δ 3.49 (d, J=14.0 Hz, 1H), 3.40 (d, J=14.0 Hz,1H), 3.37-3.32 (m, 1H), 3.17-3.09 (m, 1H), 2.05-1.86 (m, 3H), 1.86-1.70(m, 3H), 1.70-1.61 (m, 1H), 1.61-1.43 (m, 1H), 1.19 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₉H₁₉N₂: 155.15; found: 155.1.

Step 5

The mixture of compound 9-E, compound 1-E (314 mg, 0.907 mmol), andNaHCO₃ (305 mg, 3.631 mmol) in water (3 mL) and EtOH (3 mL) was stirredat room temperature. After 1 hour, the reaction mixture was concentratedto dryness and the residue was dissolved in CH₂Cl₂ before drying(MgSO₄). After the dried solution was concentrated, the residue wasdissolved in CH₂Cl₂ (1.5 mL) and 4 N HCl in dioxane (4.5 mL). Afterstirred at room temperature for 20 min, the solution was concentrated todryness and co-evaporated with toluene.

A suspension of the residue and DBU (0.7 mL, 4.681 mmol) in toluene (7mL) was stirred at 100° C. bath for 20 min. After the mixture wasconcentrated, the residue was purified by column chromatography onsilica gel using ethyl acetate-20% MeOH/ethyl acetate as eluents toobtain compound 9-F

¹H NMR (400 MHz, Chloroform-d) δ 8.21 (s, 1H), 7.64 (dd, J=7.2, 1.4 Hz,2H), 7.36-7.22 (m, 3H), 5.49 (d, J=9.9 Hz, 1H), 5.17 (d, J=9.9 Hz, 1H),4.39 (q, J=7.1 Hz, 2H), 4.15-4.06 (m, 1H), 4.01 (d, J=12.7 Hz, 1H),3.48-3.33 (m, 2H), 1.67 (s, 3H), 1.65-1.48 (m, 2H), 1.39 (t, J=7.1 Hz,3H), 1.48-1.30 (m, 3H), 1.17 (s, 3H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₅H₂₉N₂O₅: 437.21; found: 437.3.

Step 6

A mixture of compound 9-F (243 mg, 0.557 mmol) in THF (2 mL) and EtOH (2mL) was stirred at room temperature as 1 N KOH (1.15 mL) was added.After 30 min, the reaction mixture was diluted with water and acidifiedwith 1 N HCl (1.5 mL), the product was extracted with CH₂Cl₂ (×2). Thecombined extracts were dried (MgSO₄), concentrated, and dried undervacuum to obtain compound 9-G.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₂₅N₂O₅: 409.18; found: 409.2.

Step 7

A mixture of compound 9-G (188 mg, 0.460 mmol),2,4,6-trifluorobenzylamine (99 mg, 0.614 mmol), and HATU (270 mg, 0.710mmol) in CH₂Cl₂ (5 mL) was stirred at room temperature as DIPEA (0.595mL, 3.414 mmol) was added. After 30 min, the reaction mixture wasdiluted with ethyl acetate, and washed with saturated NH₄Cl (×2),water), saturated NaHCO₃ (×2), and brine. After the aqueous fractionswere extracted with ethyl acetate, the two organic fractions werecombined, dried (MgSO₄) and concentrated. The residue was purified bycolumn chromatography on silica gel using ethyl acetate-20% MeOH/ethylacetate as eluents to obtain compound 9-H.

¹H NMR (400 MHz, Chloroform-d) δ 10.48-10.31 (m, 1H), 8.36 (s, 1H), 7.57(dt, J=6.1, 1.5 Hz, 2H), 7.37-7.21 (m, 3H), 6.74-6.57 (m, 2H), 5.40 (d,J=10.0 Hz, 1H), 5.18 (d, J=10.0 Hz, 1H), 4.69 (dd, J=14.5, 5.7 Hz, 1H),4.61 (dd, J=14.5, 5.5 Hz, 1H), 4.04 (s, 2H), 3.43 (d, J=12.2 Hz, 1H),3.36 (d, J=12.2 Hz, 1H), 1.73-1.52 (m, 4H), 1.52-1.27 (m, 4H), 1.17 (s,3H).

¹⁹F NMR (377 MHz, Chloroform-d) δ −72.06 (s 1F), −109.08, −111.85 (s,2F). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₃₀H₂₉F₃N₃O₄: 552.21; found:552.3.

Step 8

Compound 9-H (200 mg, 0.363 mmol) was dissolved in TFA (2 mL) andstirred at room temperature. After 30 min, the solution was concentratedand the residue was dissolved in CH₂Cl₂ before washing with 0.1 N HCl.After the aqueous fraction was extracted with CH₂Cl₂ (×2), the organicfractions were combined, dried (MgSO₄), and concentrated. The residuewas purified by column chromatography on silica gel using CH₂Cl₂-20%MeOH in CH₂Cl₂ as eluents to obtain compound 9.

¹H NMR (400 MHz, Chloroform-d) δ 10.42 (s, 1H), 8.62-7.93 (m, 1H),6.76-6.53 (m, 2H), 4.71-4.56 (m, 2H), 4.24-3.94 (m, 2H), 3.61 (d, J=12.3Hz, 1H), 3.35-3.20 (d, J=12.3 Hz, 1H), 1.87-1.71 (m, 4H), 1.66 (d, J=8.7Hz, 1H), 1.58-1.36 (m, 3H), 1.22 (s, 3H).

¹⁹F NMR (377 MHz, Chloroform-d) δ −108.11-−110.11 (s, 1F), −111.95 (s,2F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₂₃F₃N₃O₄: 462.16; found:462.3.

Example 10 Preparation of Compound 10

Step 1

A mixture of compound 1-E (300 mg, 0.876 mmol), compound 10-A(Tetrahedron: Asymmetry 2006, 17, 252-258; 220 mg, 0.837 mmol), andNaHCO₃ (156 mg, 1.857 mmol) in water (3 mL) and EtOH (3 mL) was stirredat room temperature. After 2 hours, the reaction mixture was dilutedwith water and extracted with ethyl acetate. After the extracts werewashed with water, the organic fractions were combined, dried (Na₂SO₄),and concentrated. The residue was dried under vacuum and used for thenext reaction.

To a solution of the above residue in CH₂Cl₂ (2 mL) was added 4 N HCl indioxane (4 mL) at room temperature. After 1.5 hours, the solution wasconcentrated and dried in vacuum for 1 hour. A suspension of the residueand DBU (0.55 mL, 3.678 mmol) in toluene (5 mL) was stirred at 110° C.bath for 30 min. After the mixture was concentrated, the residue waspurified by column chromatography on silica gel using ethyl acetate-20%MeOH/ethyl acetate as eluent to obtain compound 10-B.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₂₅N₂O₅: 409.18; found 409.4.

Step 2 and Step 3

A solution of compound 10-B (200 mg, 0.49 mmol) in THF (2 mL) and MeOH(2 mL) was stirred at room temperature as 1N KOH (0.35 mL) was added.After 2.25 hours, the reaction mixture was concentrated, acidified with1 N HCl (˜0.4 mL), and diluted with brine before extraction with CH₂Cl₂.The combined extracts were dried (Na₂SO₄) and concentrated. Theresulting crude 10-C was used for the next reaction directly.

A mixture of the crude 10-C, 2,4-difluorobenzylamine (40 mg, 0.355mmol), and HATU (93 mg, 0.245 mmol) in CH₂Cl₂ (3 mL) was stirred at roomtemperature as DIPEA (0.20 mL, 1.148 mmol) was added. After 30 min, thereaction mixture was diluted with ethyl acetate, and washed withsaturated NH₄Cl, water, saturated NaHCO₃, and brine. After the aq.fractions were extracted with ethyl acetate, the organic fractions werecombined, dried (Na₂SO₄) and concentrated. The resulting residue waspurified by column chromatography on silica gel using ethyl acetate-20%MeOH/ethyl acetate as eluent to obtain compound 10-D:

¹H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 7.60 (d, J=7.4 Hz, 2H),7.45-7.36 (m, 1H), 7.36-7.27 (m, 3H), 6.90-6.73 (m, 2H), 5.38 (d, J=9.9Hz, 1H), 5.20 (d, J=9.9 Hz, 1H), 4.74-4.56 (m, 2H), 4.49 (d, J=12.9 Hz,1H), 4.23 (d, J=12.9 Hz, 1H), 3.61 (dt, J=11.4, 3.0 Hz, 1H), 3.45 (d,J=11.2 Hz, 1H), 2.74 (s, 1H), 1.92 (dd, J=16.5, 7.4 Hz, 2H), 1.71 (d,J=9.7 Hz, 1H), 1.67-1.57 (m, 1H), 1.57-1.46 (m, 2H), 1.36-1.12 (m, 3H),0.94-0.63 (m, 1H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₈H₂₆F₂N₃O₄: 506.19; found506.6.

Step 4

Compound 10-D (90 mg, 0.146 mmol) was dissolved in TFA (1 mL) andstirred at room temperature. After 30 min, the solution was concentratedand the residue was purified by column chromatography on silica gelusing CH₂Cl₂-20% MeOH in CH₂Cl₂ as eluents to obtain compound 10(3R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-2,3,4,6,8,12-hexahydro-1H-3,12a-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide:

¹H NMR (400 MHz, Acetonitrile-d3) δ 12.75 (s, 1H), 10.46 (s, 1H), 8.37(s, 1H), 7.46-7.40 (m, 1H), 7.00-6.93 (m, 2H), 4.60-4.56 (m, 2H),4.53-4.40 (m, 2H), 3.51-3.43 (m, 2H), 2.72 (s, 1H), 1.86-1.71 (m, 3H),1.61-1.53 (m, 2H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₄: 416.14; found416.3.

Example 11 Preparation of Compound 11

Compound 11 was synthesized as described above for compound 10, using(220 mg, 0.837 mmol) of compound 11-A (Tetrahedron: Asymmetry 2006, 17,252-258) in place of compound 10-A.

¹H NMR (400 MHz, acetonitrile-d3) δ 12.75 (s, 1H), 10.46 (s, 1H), 8.37(s, 1H), 7.42 (m, 1H), 6.99-6.93 (m, 2H), 4.59 (d, J=6.0 Hz, 2H), 4.47(q, J=12.8 Hz, 2H), 3.55-3.42 (m, 2H), 2.75 (s, 1H), 1.93 (m, 2H),1.82-1.79 (m, 3H), 1.60-1.53 (m, 2H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₄: 416.14; found416.3.

Example 12 Preparation of Compound 12

Step 1

To compound 11-C (0.0850 g, 0.223 mmol) and 2,4,6-trifluorobenzylamine(0.0701 g, 0.435 mmol, 2 equiv.) in CH₂Cl₂ (5 mL) was added DIPEA (0.28mL, 1.56 mmol, 7 equiv.) and HATU (0.1277 g, 0.335 mmol, 1.5 equiv.).After 60 minutes, the reaction was diluted with CH₂Cl₂ (10 mL), andwashed with sat. NH₄Cl (10 mL) and water (10 mL). The combined aqueouslayers were extracted with CH₂Cl₂ (2×20 mL). The combined organics weredried over Na₂SO₄, concentrated in vacuo and purified by columnchromatography on silica gel (0-10% MeOH:EtOAc) to obtain compound 12-A.

¹H NMR (400 MHz, DMSO-d₆) δ −10.45 (t, J=5.8 Hz, 1H), 8.53 (s, 1H), 8.18(s, OH), 7.63-7.45 (m, 2H), 7.39-7.27 (m, 3H), 7.21 (dd, J=9.2, 8.1 Hz,2H), 5.12 (d, J=10.3 Hz, 1H), 5.01 (d, J=10.3 Hz, 1H), 4.79 (d, J=13.2Hz, 1H), 4.57 (dd, J=8.7, 3.7 Hz, 2H), 3.62 (pd, J=6.6, 3.9 Hz, 1H),3.29-3.22 (m, 1H), 3.14 (qd, J=7.3, 4.2 Hz, 1H), 2.63 (s, 1H), 1.83 (d,J=9.3 Hz, 2H), 1.71-1.58 (m, 2H), 1.43 (q, J=11.1 Hz, 2H).

¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.28 (tt, J=9.3, 6.4 Hz), −112.37 (t,J=7.2 Hz).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₈H₂₅F₃N₃O₄: 524.18; found:524.14.

Step 2

To compound 12-A (0.117 g, 0.223 mmol) was added trifluoroacetic acid (5mL). After 40 minutes, the mixture was concentrated in vacuo.Trituration with Et₂O provided compound 12.

¹H NMR (400 MHz, DMSO-d₆) δ 12.58 (s, 1H), 10.42 (t, J=5.8 Hz, 1H), 8.43(s, 1H), 7.20 (t, J=8.6 Hz, 2H), 4.81 (d, J=13.2 Hz, 1H), 4.57-4.47 (m,3H), 3.44 (m, 2H), 2.69 (m, 1H), 1.89 (m, 2H), 1.72 (m 3H), 1.51 (m,1H), 1.25 (m, 2H).

¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.35 (ddd, J=15.4, 9.3, 6.3 Hz), −112.48(t, J=7.3 Hz).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₁₉F₃N₃O₄: 434.13; found:434.28.

Example 13 Preparation of Compound 13

Compound 13 is synthesized as described above for compound 10, except2,4,6-difluorobenzyl amine (0.0701 g, 0.435 mmol, 2 equiv.) was used inStep 3 rather than 2,4-difluorobenzyl amine.

Step 1

To 10-C (0.0601 g, 0.158 mmol) and 2,4,6-trifluorobenzylamine (0.0463 g,0.287 mmol, 1.8 equiv.) in CH₂Cl₂ (5 mL) was added DIPEA (0.20 mL, 1.10mmol, 7 equiv.) and HATU (0.0953 g, 0.237 mmol, 1.5 equiv.). After 60minutes, the reaction was diluted with CH₂Cl₂ (10 mL), and washed withsat. NH₄Cl (10 mL) and water (10 mL). The combined aqueous layers wereextracted with CH₂Cl₂ (2×20 mL). The combined organics were dried overNa₂SO₄ and concentrated in vacuo. Purification by column chromatographyon silica gel (0-10% MeOH:EtOAc) afforded 13-A (0.1064 g, 97%). ¹H NMR(400 MHz, DMSO-d₆) δ 10.45 (t, J=5.8 Hz, 1H), 8.53 (s, 1H), 7.61-7.45(m, 2H), 7.38-7.27 (m, 3H), 7.27-7.16 (m, 2H), 5.12 (d, J=10.3 Hz, 1H),5.01 (d, J=10.3 Hz, 1H), 4.79 (d, J=13.2 Hz, 1H), 4.62-4.50 (m, 3H),3.62 (pd, J=6.5, 3.8 Hz, 1H), 3.26 (d, J=10.9 Hz, 1H), 3.14 (qd, J=7.3,4.2 Hz, 1H), 1.83 (d, J=9.3 Hz, 2H), 1.71-1.59 (m, 2H), 1.42 (p, J=10.1,9.4 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.21-−109.34 (m), −112.38(t, J=7.3 Hz). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₈H₂₅F₃N₃O₄:524.18; found: 524.28.

Step 2

To 13-A (0.083 g, 0.159 mmol) was added trifluoroacetic acid (5 mL).After 45 minutes, the mixture was concentrated in vacuo. Triturationwith Et₂O afforded 13.

¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (s, 1H), 10.42 (t, J=5.8 Hz, 1H), 8.43(s, 1H), 7.20 (t, J=8.6 Hz, 2H), 4.81 (d, J=13.2 Hz, 1H), 4.55 (d, J=5.8Hz, 2H), 4.51 (d, J=13.0 Hz, 1H), 3.50 3.40 (m, 2H), 2.68 (m, 1H), 1.89(m, 2H), 1.73 (m, 3H), 1.55 1.42 (m, 1H), 1.25 (m, 2H).

¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.36 (ddd, J=15.5, 9.6, 6.4 Hz), −112.49(t, J=7.3 Hz).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₁₉F₃N₃O₄: 434.13; found:434.21.

Example 14 Preparation of Compound 14

Step 1

A mixture of compound 3-G (75 mg, 0.184 mmol) in THF (1.25 mL) and MeOH(1.25 mL) was stirred at room temperature as 1 N KOH (0.97 mL) wasadded. After 30 minutes at room temperature, the reaction mixture wasconcentrated and diluted with water before washing with ether (×1). Theaqueous fraction was acidified with 1 N HCl (˜3.3 mL), and extacted withethyl acetate (×2). The extracts were washed with brine (×1), combined,dried (Na₂SO₄), and concentrated to provide the crude acid.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₁N₂O₅: 381.15; found:381.09.

A mixture of the crude acid from the previous step (64 mg, 0.168 mmol),(R)-1-(2,4,6-trifluorophenyl)ethylamine (34 mg, 0.193 mmol), and HATU(83 mg, 0.219 mmol) in DMF (2 mL) was stirred at room temperature asDIPEA (0.21 mL, 1.178 mmol) was added. After 2 hours, the mixture wasdiluted with ethyl acetate, washed with saturated NH₄Cl and saturatedNaHCO₃. After the aqueous fractions were extracted with ethyl acetate,the organic fractions were combined, dried (Na₂SO₄), and concentrated toprovide compound 14-A.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₉H₂₇F₃N₃O₄: 538.20; found:538.06.

Step 2

Compound 14-A (85 mg, 0.158 mmol) was dissolved and stirred in TFA (1.2mL) at room temperature. After 15 minutes, the solution was concentratedand the residue was purified by preparative HPLC and the collectedfraction was freeze-dried to provide compound 14.

¹H NMR (400 MHz, Chloroform-d) δ 10.76 (d, J=8.1 Hz, 1H), 8.36 (s, 1H),6.63 (t, J=8.4 Hz, 2H), 5.64 (p, J=7.4 Hz, 1H), 4.81 (t, J=4.8 Hz, 1H),4.50 4.16 (m, 2H), 2.10-1.43 (m, 12H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₁F₃N₃O₄: 448.15; found:448.18.

Example 15 Preparation of Compound 15

Step 1

A mixture of compound 3-G (165 mg, 0.404 mmol) in THF (2.5 mL) and MeOH(2.5 mL) was stirred at room temperature as 1 N KOH (2.13 mL) was added.After 30 minutes at room temperature, the reaction mixture wasconcentrated and diluted with water, acidified with 1 N HCl, andextracted with ethyl acetate (×2). The extracts were combined, dried(Na₂SO₄), and concentrated to provide the crude acid.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₁N₂O₅: 381.15; found:381.13.

A mixture of the crude acid from the previous step (150 mg, 0.394 mmol),2,4,6-trifluorobenzylamine (76 mg, 0.47 mmol), and HATU (188 mg, 0.49mmol) in DMF (3 mL) was stirred at room temperature as DIPEA (0.48 mL,2.76 mmol) was added. After 2 hours, additional2,4,6-trifluorobenzylamine (32 mg, 0.20 mmol), HATU (105 mg, 0.28 mmol),and DIPEA (0.14 mL, 0.79 mmol) were added and the resulting mixture wasstirred at room temperature. After 2 days, additional2,4,6-trifluorobenzylamine (32 mg, 0.20 mmol), HATU (105 mg, 0.28 mmol),and DIPEA (0.14 mL, 0.79 mmol) were added and the resulting mixture wasstirred at room temperature for 2 hours. The mixture was diluted withwater, extracted with ethyl acetate (×3), and combined extracts weredried (Na₂SO₄), and concentrated to provide crude compound 15-A.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₈H₂₅F₃N₃O₄: 524.18; found:524.15.

Step 2

Compound 15-A (205 mg, 0.392 mmol) was dissolved and stirred in TFA (3mL) at room temperature. After 15 minutes, the solution was concentratedand the residue was purified by preparative HPLC and the collectedfraction was freeze-dried to provide compound 15.

¹H NMR (400 MHz, DMSO-d₆) δ 12.65 (s, 1H), 10.38 (t, J=5.8 Hz, 1H), 8.44(s, 1H), 7.30 7.07 (m, 2H), 4.65 (m, 3H), 4.55 (d, J=5.7 Hz, 2H),1.91-1.75 (m, 4H), 1.69 (dtt, J=21.9, 9.5, 3.9 Hz, 4H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₁₉F₃N₃O₄: 434.13; found:434.19.

Antiviral Assay Example 16 Antiviral Assays in MT4 Cells

For the antiviral assay utilizing MT4 cells, 0.4 μL of 189× testconcentration of 3-fold serially diluted compound in DMSO was added to40 μL of cell growth medium (RPMI 1640, 10% FBS, 1%penicilline/Streptomycine, 1% L-Glutamine, 1% HEPES) in each well of384-well assay plates (10 concentrations) in quidruplicate.

1 mL aliquots of 2×10⁶ MT4 cells are pre-infected for 1 and 3 hoursrespectively at 37° C. with 25 μL (MT4) or of either cell growth medium(mock-infected) or a fresh 1:250 dilution of an HIV-IIIb concentratedABI stock (0.004 m.o.i. for MT4 cells). Infected and uninfected cellsare diluted in cell growth medium and 35 μL of 2000 (for MT4) cells isadded to each well of the assay plates.

Assay plates were then incubated in a 37° C. incubator. After 5 days ofincubation, 25 μL of 2× concentrated CellTiter-Glo™ Reagent (catalog #G7573, Promega Biosciences, Inc., Madison, Wis.) was added to each wellof the assay plate. Cell lysis was carried out by incubating at roomtemperature for 2-3 minutes, and then chemiluminescence was read usingthe Envision reader (PerkinElmer).

Compounds of the present invention demonstrate antiviral activity inthis assay as depicted in Table 1 below. Accordingly, the compounds ofthe invention may be useful for treating the proliferation of the HIVvirus, treating AIDS, or delaying the onset of AIDS or ARC symptoms.

TABLE 1 Compound nM in MT-4 Number EC₅₀ CC₅₀ 1 3.5 49911 2 4.4 53192 31.9 26191 4 1.6 10963 5 1.3 10630 6 2.6 9659 7 2.8 12992 8 2.3 5303 91.4 8665 10 2.3 24021 11 3.2 27861 12 3.2 53192 13 1.7 24340 14 6.213196 15 2.3 24021

The data in Table 1 represent an average over time for each compound.For certain compounds, multiple assays have been conducted over the lifeof the project. Thus, the data reported in Table 1 include the datareported in the priority documents, as well as data from assays run inthe intervening period.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference, in their entirety to the extent notinconsistent with the present description.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

What is claimed is:
 1. A compound having a Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: L is—C(R^(a))₂—; X is —CHR²—; W is —CHR³—; Z is —CHR⁴—; each R^(a) isindependently hydrogen, halogen, hydroxy or C₁₋₄alkyl; R¹ is phenyl,substituted with one, two or three halogens; R² is hydrogen orC₁₋₃alkyl; R³ is hydrogen or C₁₋₃alkyl; R⁴ is hydrogen or C₁₋₃alkyl; R⁵is hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl; Y¹ is hydrogen, C₁₋₃alkyl orC₁₋₃haloalkyl; and Y² is hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R^(a) is independently hydrogen.
 3. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl,substituted with one halogen.
 4. The compound of claim 3, or apharmaceutically acceptable salt thereof, wherein R¹ is 2-fluorophenylor 4-fluorophenyl.
 5. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is phenyl, substituted with twohalogens.
 6. The compound of claim 5, or a pharmaceutically acceptablesalt thereof, wherein R¹ is 2,3-difluorophenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,3-chloro-2-fluorophenyl, 4-chloro-2-fluorophenyl or4-chloro-3-fluorophenyl.
 7. The compound of claim 5, or apharmaceutically acceptable salt thereof, wherein R¹ is2,3-difluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 4-chloro-2-fluorophenyl or4-chloro-3-fluorophenyl.
 8. The compound of claim 7, or apharmaceutically acceptable salt thereof, wherein R¹ is2,4-difluorophenyl.
 9. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is phenyl, substituted with threehalogens.
 10. The compound of claim 9, or a pharmaceutically acceptablesalt thereof, wherein R¹ is 2,3,4-trifluorophenyl or2,4,6-trifluorophenyl.
 11. The compound of claim 10, or apharmaceutically acceptable salt thereof, wherein R¹ is2,4,6-trifluorophenyl.
 12. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen orC₁₋₃alkyl.
 13. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁵ is hydrogen.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is methyl.
 15. Thecompound of claim 1, wherein the compound has Formula (II):

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim15, wherein the compound has Formula (II-A):

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier, diluent orexcipient and the compound of claim 1, or a pharmaceutically acceptablesalt thereof.
 18. A method for modulating human immunodeficiency virusproliferation in a human, comprising administering to the human in needthereof a therapeutically effective amount of the compound of claim 1,or a pharmaceutically acceptable salt thereof.
 19. The method of claim18, wherein the human is at risk of having a human immunodeficiencyvirus infection or the human has a human immunodeficiency virusinfection.
 20. A compound having a Formula (I-A):

or a pharmaceutically acceptable salt thereof, wherein: L is—C(R^(a))₂—; X is —CHR²—; W is —CHR³—; Z is —CHR⁴—; each R^(a) isindependently hydrogen, halogen, hydroxy or C₁₋₄alkyl; R¹ is phenyl,substituted with one, two or three halogens; R² is hydrogen orC₁₋₃alkyl; R³ is hydrogen or C₁₋₃alkyl; R⁴ is hydrogen or C₁₋₃alkyl; Y¹is hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl; and Y² is hydrogen, C₁₋₃alkylor C₁₋₃ haloalkyl.
 21. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.